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Morikawa, Hirofumi, Takashi Morishita, Shiho Kawane, Hiroshi Iwasaki, Antony M. Carr, and Hideo Shinagawa. "Rad62 Protein Functionally and Physically Associates with the Smc5/Smc6 Protein Complex and Is Required for Chromosome Integrity and Recombination Repair in Fission Yeast." Molecular and Cellular Biology 24, no. 21 (November 1, 2004): 9401–13. http://dx.doi.org/10.1128/mcb.24.21.9401-9413.2004.
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ABSTRACT Smc5 and Smc6 proteins form a heterodimeric SMC (structural maintenance of chromosome) protein complex like SMC1-SMC3 cohesin and SMC2-SMC4 condensin, and they associate with non-SMC proteins Nse1 and Nse2 stably and Rad60 transiently. This multiprotein complex plays an essential role in maintaining chromosome integrity and repairing DNA double strand breaks (DSBs). This study characterizes a Schizosaccharomyces pombe mutant rad62-1, which is hypersensitive to methyl methanesulfonate (MMS) and synthetically lethal with rad2 (a feature of recombination mutants). rad62-1 is hypersensitive to UV and gamma rays, epistatic with rhp51, and defective in repair of DSBs. rad62 is essential for viability and genetically interacts with rad60, smc6, and brc1. Rad62 protein physically associates with the Smc5-6 complex. rad62-1 is synthetically lethal with mutations in the genes promoting recovery from stalled replication, such as rqh1, srs2, and mus81, and those involved in nucleotide excision repair like rad13 and rad16. These results suggest that Rad62, like Rad60, in conjunction with the Smc5-6 complex, plays an essential role in maintaining chromosome integrity and recovery from stalled replication by recombination.
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Guacci, Vincent, and Douglas Koshland. "Cohesin-independent segregation of sister chromatids in budding yeast." Molecular Biology of the Cell 23, no. 4 (February 15, 2012): 729–39. http://dx.doi.org/10.1091/mbc.e11-08-0696.
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Cohesin generates cohesion between sister chromatids, which enables chromosomes to form bipolar attachments to the mitotic spindle and segregate. Cohesin also functions in chromosome condensation, transcriptional regulation, and DNA damage repair. Here we analyze the role of acetylation in modulating cohesin functions and how it affects budding yeast viability. Previous studies show that cohesion establishment requires Eco1p-mediated acetylation of the cohesin subunit Smc3p at residue K113. Smc3p acetylation was proposed to promote establishment by merely relieving Wpl1p inhibition because deletion of WPL1 bypasses the lethality of an ECO1 deletion (eco1Δ wpl1Δ). We find that little, if any, cohesion is established in eco1Δ wpl1Δ cells, indicating that Eco1p performs a function beyond antagonizing Wpl1p. Cohesion also fails to be established when SMC3 acetyl-mimics (K113Q or K112R,K113Q) are the sole functional SMC3s in cells. These results suggest that Smc3p acetylation levels affect establishment. It is remarkable that, despite their severe cohesion defect, eco1Δ wpl1Δ and smc3-K112R,K113Q strains are viable because a cohesin-independent mechanism enables bipolar attachment and segregation. This alternative mechanism is insufficient for smc3-K113Q strain viability. Smc3-K113Q is defective for condensation, whereas eco1Δ wpl1Δ and smc3-K112R,K113Q strains are competent for condensation. We suggest that Smc3p acetylation and Wpl1p antagonistically regulate cohesin's essential role in condensation.
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Eijpe, M., C. Heyting, B. Gross, and R. Jessberger. "Association of mammalian SMC1 and SMC3 proteins with meiotic chromosomes and synaptonemal complexes." Journal of Cell Science 113, no. 4 (February 15, 2000): 673–82. http://dx.doi.org/10.1242/jcs.113.4.673.
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In somatic cells, the heterodimeric Structural Maintenance of Chromosomes (SMC) proteins are involved in chromosome condensation and gene dosage compensation (SMC2 and 4), and sister chromatid cohesion and DNA recombination (SMC1 and 3). We report here evidence for an involvement of mammalian SMC1 and SMC3 proteins in meiosis. Immunofluorescence analysis of testis sections showed intense chromatin association in meiotic prophase cells, weaker staining in round spermatids and absence of the SMC proteins in elongated spermatids. In spermatocyte nuclei spreads, the SMC1 and SMC3 proteins localize in a beaded structure along the axial elements of synaptonemal complexes of pachytene and diplotene chromosomes. Both SMC proteins are present in rat spermatocytes and enriched in preparations of synaptonemal complexes. Several independent experimental approaches revealed interactions of the SMC proteins with synaptonemal complex-specific proteins SCP2 and SCP3. These results suggest a model for the arrangement of SMC proteins in mammalian meiotic chromatin.
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Eng, Thomas, Vincent Guacci, and Douglas Koshland. "Interallelic complementation provides functional evidence for cohesin–cohesin interactions on DNA." Molecular Biology of the Cell 26, no. 23 (November 15, 2015): 4224–35. http://dx.doi.org/10.1091/mbc.e15-06-0331.
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The cohesin complex (Mcd1p, Smc1p, Smc3p, and Scc3p) has multiple roles in chromosome architecture, such as promoting sister chromatid cohesion, chromosome condensation, DNA repair, and transcriptional regulation. The prevailing embrace model for sister chromatid cohesion posits that a single cohesin complex entraps both sister chromatids. We report interallelic complementation between pairs of nonfunctional mcd1 alleles (mcd1-1 and mcd1-Q266) or smc3 alleles (smc3-42 and smc3-K113R). Cells bearing individual mcd1 or smc3 mutant alleles are inviable and defective for both sister chromatid cohesion and condensation. However, cells coexpressing two defective mcd1 or two defective smc3 alleles are viable and have cohesion and condensation. Because cohesin contains only a single copy of Smc3p or Mcd1p, these examples of interallelic complementation must result from interplay or communication between the two defective cohesin complexes, each harboring one of the mutant allele products. Neither mcd1-1p nor smc3-42p is bound to chromosomes when expressed individually at its restrictive temperature. However, their chromosome binding is restored when they are coexpressed with their chromosome-bound interallelic complementing partner. Our results support a mechanism by which multiple cohesin complexes interact on DNA to mediate cohesion and condensation.
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Mito, Yoshiko, Asako Sugimoto, and Masayuki Yamamoto. "Distinct Developmental Function of Two Caenorhabditis elegans Homologs of the Cohesin Subunit Scc1/Rad21." Molecular Biology of the Cell 14, no. 6 (June 2003): 2399–409. http://dx.doi.org/10.1091/mbc.e02-09-0603.
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Cohesin, which mediates sister chromatid cohesion, is composed of four subunits, named Scc1/Rad21, Scc3, Smc1, and Smc3 in yeast. Caenorhabditis elegans has a single homolog for each of Scc3, Smc1, and Smc3, but as many as four for Scc1/Rad21 (COH-1, SCC-1/COH-2, COH-3, and REC-8). Except for REC-8 required for meiosis, function of these C. elegans proteins remains largely unknown. Herein, we examined their possible involvement in mitosis and development. Embryos depleted of the homolog of either Scc3, or Smc1, or Smc3 by RNA interference revealed a defect in mitotic chromosome segregation but not in chromosome condensation and cytokinesis. Depletion of SCC-1/COH-2 caused similar phenotypes. SCC-1/COH-2 was present in cells destined to divide. It localized to chromosomes in a cell cycle-dependent manner. Worms depleted of COH-1 arrested at either the late embryonic or the larval stage, with no indication of mitotic dysfunction. COH-1 associated chromosomes throughout the cell cycle in all somatic cells undergoing late embryogenesis or larval development. Thus, SCC-1/COH-2 and the homologs of Scc3, Smc1, and Smc3 facilitate mitotic chromosome segregation during the development, presumably by forming a cohesin complex, whereas COH-1 seems to play a role important for development but unrelated to mitosis.
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Viny, Aaron D., Christopher J. Ott, Barbara Spitzer, Martin A. Rivas, Cem Meydan, Efthymia Papalexi, Dana Yelin, et al. "Dose-Dependent Role of the Cohesin Complex in Normal and Malignant Hematopoiesis." Blood 126, no. 23 (December 3, 2015): 435. http://dx.doi.org/10.1182/blood.v126.23.435.435.
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Abstract Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation, however cohesin-mutant leukemias do not show genomic instability suggesting an alternate role in malignant transformation. We hypothesized reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic stem/progenitor cells. We therefore investigated the impact of both complete loss and haploinsufficiency of Smc3, an obligate member of the cohesin complex, in normal hematopoiesis and in myeloid transformation by developing a conditional Smc3 knockout allele. Somatic loss of Smc3 in hematopoietic cells induced lethal bone marrow aplasia (median survival 11 days; p<0.001), with premature sister chromatid separation and abnormal nucleolar organization. Competitive transplant assays showed that Smc3 loss completely abrogated stem cell self-renewal in vivo. These data are consistent with an absolute requirement for the cohesin complex in hematopoietic stem/progenitor cells. By contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo, with increased serial replating, expanded hematopoietic stem/progenitor cells, and a self-renewal/engraftment advantage in competitive transplantation assays in vivo (Figure a). Smc3 haploinsufficiency altered coordinated transcriptional output, including reduced expression of master regulatory transcription factors governing lineage commitment. Consistent with these data, Smc3 loss resulted in expanded Cd150+ Cd48+ ST-HSC (p=0.008), reduction in Cd150+ Cd48- LT-HSC (p=0.001), and altered chromatin architecture with dysregulated expression of genes with specific chromatin architecture footprints. Smc3 haploinsufficiency cooperated with Flt3ITD to induce acute leukemia in vivo (Figure b), with dysregulated expression of hematopoietic master regulators and altered nucleolar topology similar to that observed in germline cohesinopathy syndromes and in AML patients with cohesin mutations (Figure c). To further explore the mechanism by which Smc3 loss cooperates with Flt3ITD to induce leukemia, we investigated chromatin cis-regulatory architecture with transposase hypersensitivity assays (ATAC-seq). We hypothesized that increased accessibility at cis-regulatory elements and the alterations in gene expression seen in cells with combined Smc3 haploinsufficiency and Flt3ITD may be in a large part driven by potentiated Stat signaling at chromatin. We analyzed 146 transcription factor recognition motifs within the THS differentially observed in Smc3Δ/+Flt3ITD and wild-type cells. Chromatin accessibility gained in Smc3Δ/+Flt3ITD cells are enriched in Stat family transcription factor binding sites, including Stat5. We also observed enrichment of the Stat5 gene expression signature in the Smc3Δ/+Flt3ITD cells compared to Smc3Δ/+, Flt3ITD and wild-type cells, suggesting the divergent mutations cooperate to potentiate oncogenic Stat5 signaling in HSPCs. Our results demonstrate a key dose-dependent role for the cohesin complex in hematopoiesis, and show that reduced cohesin functions to alter enhancer-mediated transcription and contribute to aberrant self-renewal and myeloid transformation. Figure 1. Figure 1. Disclosures Levine: Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Consultancy.
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Kuan, Lídia, Frederico Pratas, Leonel Sousa, and Pedro Tomás. "MrBayes sMC3." International Journal of High Performance Computing Applications 32, no. 2 (June 30, 2016): 246–65. http://dx.doi.org/10.1177/1094342016652461.
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MrBayes is a popular software package for Bayesian phylogenetic inference, which uses an iterative approach to derive an evolutionary tree for a collection of species whose DNA sequences are known. Computationally, MrBayes is characterized by a large number of iterations, each composed of a set of tasks that isolated are not very time-consuming, but are globally computationally demanding. To accelerate the latest MrBayes 3.2, this paper presents MrBayes sMC3, which relies on the computational power of an heterogeneous CPU+GPU platform. For this, MrBayes sMC3 exploits both task and data-level parallelism while minimizing the overheads associated with kernel launches and CPU-GPU data transfers. Experimental results indicate that the proposed parallel approach, together with the proposed set of optimizations, allow for an application acceleration of up to 10× regarding the original MrBayes, and up to 3× regarding the Beagle Library. Furthermore, by analyzing the convergence rate of MrBayes sMC3 with that of the state-of-the-art approaches, a significant reduction in execution time is observed.
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Lu, Zhanping, Anna L. F. V. Assumpção, Aaron D. Viny, Ross L. Levine, and Xuan Pan. "YY1 Controls Hematopoietic Stem Cell Quiescence By Repressing Cohesin Expression." Blood 132, Supplement 1 (November 29, 2018): 3831. http://dx.doi.org/10.1182/blood-2018-99-118679.
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Abstract Hematopoietic stem cells (HSCs) are undifferentiated, self-renewing, pluripotent cells that have the capacity to differentiate into all mature lineage-specific cells in adult blood. Adult HSCs can remain in a quiescent state for a prolonged time, and quiescence is a fundamental characteristic of HSCs in adult bone marrow. Thus, the cell cycle must be precisely regulated. Yin Yang 1 (YY1) is a multifunctional transcription factor and Polycomb Group Protein (PcG) that is important for embryonic development, adult hematopoiesis, cell proliferation and maintaining higher-order chromosomal structure. We have generated YY1 conditional knockout mice (Yy1f/f Mx1-Cre) and showed that Yy1 deficient HSCs fail to self-renewal and had disrupted HSCs quiescence. Stem cell factor (SCF)/c-Kit signaling, a critical regulatory pathway in HSC development, is significantly downregulated in Yy1-/- HSCs. Interestingly, YY1 regulation of HSCs self-renewal and quiescence is independent on its PcG domain/function. Instead, YY1 occupied at Smc3 promoter area and repressed Smc3 expression. In Yy1-/-HSCs, Smc3 expression was upregulated. SMC3 is a core component of cohesin protein complex and plays critical roles in HSC self-renewal, myeloid differentiation and leukemogenesis. To further dissect the underlying mechanisms by which YY1 regulates SMC3 expression in HSCs, we have generated conditional knockout mice with YY1 homozygous deletion and SMC3 heterozygous deletion (Yy1f/f Smc3f/+Mx1-Cre). In Yy1-/- Smc3+/- bone marrow cells, SMC3 expression was normalized to the wild-type level. In adult bone marrow cells, YY1 physically interacted with cohesin complex proteins through its zinc finger domain. By analyzing the YY1, SMC1A and SMC3 ChIP-Seq database, our study showed that YY1 and cohesin co-occupied at promoter areas of genes that are critical for cell metabolism. Evidence from previous study showed that impaired metabolism, including increased reactive oxygen species (ROS) and decreased mitochondrial function, can cause defect in stem cell self-renewal and quiescence. In Yy1-/- Smc3+/-HSCs, cell quiescence was restored although HSC self-renewal was still impaired, indicates that YY1 and SMC3 may control HSC cell quiescence via regulating genes critical for cell metabolism. Our study identified YY1 as the first transcription factor that regulates expression of cohesin complex component SMC3. We are currently further dissecting underlying mechanisms and functional significances of metabolic pathways regulated by YY1-SMC3 axis in HSCs. Disclosures Levine: Imago: Equity Ownership; Isoplexis: Equity Ownership; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Epizyme: Patents & Royalties; Loxo: Consultancy, Equity Ownership; C4 Therapeutics: Equity Ownership; Roche: Consultancy, Research Funding; Prelude: Research Funding; Qiagen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Novartis: Consultancy.
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Wang, Tianjiao, and John S. Welch. "Smc3 Haploinsufficiency and Smc3 Deletion Alter Hematopoiesis In Vivo." Blood 128, no. 22 (December 2, 2016): 2903. http://dx.doi.org/10.1182/blood.v128.22.2903.2903.
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Abstract Recurrent mutations in SMC3, encoding a cohesin subunit, have been identified in acute myeloid leukemia (AML) and other myeloid malignancies by our group and others. SMC3 mutations are heterozygous in AML patients. Missense, nonsense, and splice site mutations have been observed across all domains of SMC3. Given the breath of mutations, it is important to determine whether these represent recurrent loss-of-function mechanisms, or if some might have dominant negative effects. To determine the impact of Smc3 deletion on hematopoiesis, we studied both Smc3 haploinsufficient and Smc3 deficient mice as models of loss-of function and dominant negative phenotypes respectively. The Smc3 haploinsufficient mouse model has a lacZneo gene trap inserted in intron 3-4 of Smc3, which leads to a premature transcription stop and therefore produces a truncated and dysfunctional protein. The homozygous Smc3trap allele is embryonic lethal. The Smc3trap/+mice have an early growth defect, although their body weight catches up to wild type mice after 6 weeks of age. We found no difference in spleen weights, peripheral blood counts, and bone marrow (BM) compositions between Smc3trap/+ and wild type mice. The Smc3trap/+ BM cells formed similar number of colonies as wild type cells when plated in methylcellulose in vitro and lost self-renewal capabilities after replating for two weeks. Competitive repopulation assay in vivo showed neither advantage nor disadvantage for the Smc3trap/+BM cells (n=10). Thus, Smc3trap/+BM cells have normal colony forming capacity in vitro and normal homeostatic feedback in vivo. Further, we generated Smc3 conditionally deficient mice by removing the gene-trap cassette, which retains the loxP sites flanking exon 4 (Smc3fl), and crossing these mice with either Vav1-Cre+/- or ERT2-Cre+/- to delete the allele (Smc3fl/+/Vav1-Cre+/- is constitutively haploinsufficient in hematopoietic cells, whereas Smc3fl/+/ERT2-Cre+/-is only haploinsufficient when induced with tamoxifen). We characterized both models by serial replating assays, flow cytometry assays for hematopoietic stem/progenitor cells (HSPCs), and BM lineage in vitro and found no difference in these mice compared to the Smc3fl/+control. In contrast to the Smc3fl/+/Mx1-Cre+/- mice (Viny et al. JEM 212 (11): 1819-1832), we observed a significant competitive disadvantage for the Smc3fl/+/ERT2-Cre+/-BM cells (p<0.0001, n=10), most pronounced in Gr1+ myeloid cells in vivo (p<0.0001), implying Smc3 haploinsufficiency alters hematopoiesis in those mice in vivo. We characterized the effects of homozygous Smc3 loss on hematopoiesis in the inducible Smc3fl/fl/ERT2-Cre+/- mice by treating mice with tamoxifen at 6 weeks of age (Smc3fl/fl/Vav1-Cre+/- is embryonic lethal). Deletion of Smc3 led to rapid bone marrow failure and 100% lethality with a median survival of 8 days (n=4, 2 independent experiments). At the time of death, we observed severe reduction in the sizes of spleen (Sp) and thymus (Thy), in total number of BM, Sp, and Thy cells, and in white blood counts, lymphocytes, monocytes, and platelets. The Smc3 deficient BM cells had decreased levels of Smc3 by Western blot. The impact of Smc3 deletion on HSPC functions in vivo was assessed by a competitive repopulation assay of Smc3fl/fl/ERT2-Cre+/-BM cells (p<0.0001, n=10). Recipient mice were treated with tamoxifen after 6-week engraftment. After tamoxifen-mediated deletion, Smc3 deficient cells were rapidly outcompeted in vivo, indicating complete loss of HSPC functions. Collectively, these results suggest that Smc3 is necessary for normal hematopoiesis and for HSPC functions. The AML-associated SMC3 mutations are therefore unlikely to be dominant negative because the complete loss of Smc3 is incompatible with hematopoiesis. Disclosures No relevant conflicts of interest to declare.
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Laugsch, Magdalena, Jochen Seebach, Hans Schnittler, and Rolf Jessberger. "Imbalance of SMC1 and SMC3 Cohesins Causes Specific and Distinct Effects." PLoS ONE 8, no. 6 (June 12, 2013): e65149. http://dx.doi.org/10.1371/journal.pone.0065149.
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Guacci, Vincent, Jeremiah Stricklin, Michelle S. Bloom, Xuánzōng Guō, Meghna Bhatter, and Douglas Koshland. "A novel mechanism for the establishment of sister chromatid cohesion by the ECO1 acetyltransferase." Molecular Biology of the Cell 26, no. 1 (January 2015): 117–33. http://dx.doi.org/10.1091/mbc.e14-08-1268.
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Cohesin complex mediates cohesion between sister chromatids, which promotes high-fidelity chromosome segregation. Eco1p acetylates the cohesin subunit Smc3p during S phase to establish cohesion. The current model posits that this Eco1p-mediated acetylation promotes establishment by abrogating the ability of Wpl1p to destabilize cohesin binding to chromosomes. Here we present data from budding yeast that is incompatible with this Wpl1p-centric model. Two independent in vivo assays show that a wpl1∆ fails to suppress cohesion defects of eco1∆ cells. Moreover, a wpl1∆ also fails to suppress cohesion defects engendered by blocking just the essential Eco1p acetylation sites on Smc3p (K112, K113). Thus removing WPL1 inhibition is insufficient for generating cohesion without ECO1 activity. To elucidate how ECO1 promotes cohesion, we conducted a genetic screen and identified a cohesion activator mutation in the SMC3 head domain (D1189H). Smc3-D1189H partially restores cohesion in eco1∆ wpl1∆ or eco1 mutant cells but robustly restores cohesion in cells blocked for Smc3p K112 K113 acetylation. These data support two important conclusions. First, acetylation of the K112 K113 region by Eco1p promotes cohesion establishment by altering Smc3p head function independent of its ability to antagonize Wpl1p. Second, Eco1p targets other than Smc3p K112 K113 are necessary for efficient establishment.
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Lin, Su-Jiun, Claudia Tapia-Alveal, Omar J. Jabado, Doris Germain, and Matthew J. O’Connell. "An acetyltransferase-independent function of Eso1 regulates centromere cohesion." Molecular Biology of the Cell 27, no. 25 (December 15, 2016): 4002–10. http://dx.doi.org/10.1091/mbc.e16-08-0596.
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Eukaryotes contain three essential Structural Maintenance of Chromosomes (SMC) complexes: cohesin, condensin, and Smc5/6. Cohesin forms a ring-shaped structure that embraces sister chromatids to promote their cohesion. The cohesiveness of cohesin is promoted by acetylation of N-terminal lysines of the Smc3 subunit by the acetyltransferases Eco1 in Saccharomyces cerevisiae and the homologue, Eso1, in Schizosaccharomyces pombe. In both yeasts, these acetyltransferases are essential for cell viability. However, whereas nonacetylatable Smc3 mutants are lethal in S. cerevisiae, they are not in S. pombe. We show that the lethality of a temperature-sensitive allele of eso1 ( eso1-H17) is due to activation of the spindle assembly checkpoint (SAC) and is associated with premature centromere separation. The lack of cohesion at the centromeres does not correlate with Psm3 acetylation or cohesin levels at the centromeres, but is associated ith significantly reduced recruitment of the cohesin regulator Pds5. The SAC activation in this context is dependent on Smc5/6 function, which is required to remove cohesin from chromosome arms but not centromeres. The mitotic defects caused by Smc5/6 and Eso1 dysfunction are cosuppressed in double mutants. This identifies a novel function (or functions) for Eso1 and Smc5/6 at centromeres and extends the functional relationships between these SMC complexes.
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Sun, Mingxuan, Tatsuya Nishino, and John F. Marko. "The SMC1-SMC3 cohesin heterodimer structures DNA through supercoiling-dependent loop formation." Nucleic Acids Research 41, no. 12 (April 24, 2013): 6149–60. http://dx.doi.org/10.1093/nar/gkt303.
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Revenkova, E., M. Eijpe, C. Heyting, B. Gross, and R. Jessberger. "Novel Meiosis-Specific Isoform of Mammalian SMC1." Molecular and Cellular Biology 21, no. 20 (October 15, 2001): 6984–98. http://dx.doi.org/10.1128/mcb.21.20.6984-6998.2001.
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ABSTRACT Structural maintenance of chromosomes (SMC) proteins fulfill pivotal roles in chromosome dynamics. In yeast, the SMC1-SMC3 heterodimer is required for meiotic sister chromatid cohesion and DNA recombination. Little is known, however, about mammalian SMC proteins in meiotic cells. We have identified a novel SMC protein (SMC1β), which—except for a unique, basic, DNA binding C-terminal motif—is highly homologous to SMC1 (which may now be called SMC1α) and is not present in the yeast genome. SMC1β is specifically expressed in testes and coimmunoprecipitates with SMC3 from testis nuclear extracts, but not from a variety of somatic cells. This establishes for mammalian cells the concept of cell-type- and tissue-specific SMC protein isoforms. Analysis of testis sections and chromosome spreads of various stages of meiosis revealed localization of SMC1β along the axial elements of synaptonemal complexes in prophase I. Most SMC1β dissociates from the chromosome arms in late-pachytene-diplotene cells. However, SMC1β, but not SMC1α, remains chromatin associated at the centromeres up to metaphase II. Thus, SMC1β and not SMC1α is likely involved in maintaining cohesion between sister centromeres until anaphase II.
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Espinoza-Monje, Marcela, Jorge Campos, Eduardo Alvarez Villamil, Alonso Jerez, Stefania Dentice Maidana, Mariano Elean, Susana Salva, Haruki Kitazawa, Julio Villena, and Apolinaria García-Cancino. "Characterization of Weissella viridescens UCO-SMC3 as a Potential Probiotic for the Skin: Its Beneficial Role in the Pathogenesis of Acne Vulgaris." Microorganisms 9, no. 7 (July 13, 2021): 1486. http://dx.doi.org/10.3390/microorganisms9071486.
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Previously, we isolated lactic acid bacteria from the slime of the garden snail Helix aspersa Müller and selected Weissella viridescens UCO-SMC3 because of its ability to inhibit in vitro the growth of the skin-associated pathogen Cutibacterium acnes. The present study aimed to characterize the antimicrobial and immunomodulatory properties of W. viridescens UCO-SMC3 and to demonstrate its beneficial effect in the treatment of acne vulgaris. Our in vitro studies showed that the UCO-SMC3 strain resists adverse gastrointestinal conditions, inhibits the growth of clinical isolates of C. acnes, and reduces the adhesion of the pathogen to keratinocytes. Furthermore, in vivo studies in a mice model of C. acnes infection demonstrated that W. viridescens UCO-SMC3 beneficially modulates the immune response against the skin pathogen. Both the oral and topical administration of the UCO-SCM3 strain was capable of reducing the replication of C. acnes in skin lesions and beneficially modulating the inflammatory response. Of note, orally administered W. viridescens UCO-SMC3 induced more remarkable changes in the immune response to C. acnes than the topical treatment. However, the topical administration of W. viridescens UCO-SMC3 was more efficient than the oral treatment to reduce pathogen bacterial loads in the skin, and effects probably related to its ability to inhibit and antagonize the adhesion of C. acnes. Furthermore, a pilot study in acne volunteers demonstrated the capacity of a facial cream containing the UCO-SMC3 strain to reduce acne lesions. The results presented here encourage further mechanistic and clinical investigations to characterize W. viridescens UCO-SMC3 as a probiotic for acne vulgaris treatment.
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Viny, Aaron D., Christopher J. Ott, Barbara Spitzer, Martin Rivas, Cem Meydan, Efthymia Papalexi, Dana Yelin, et al. "Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis." Journal of Experimental Medicine 212, no. 11 (October 5, 2015): 1819–32. http://dx.doi.org/10.1084/jem.20151317.
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Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation; however, cohesin mutant leukemias do not show genomic instability. We hypothesized that reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Biallelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation and revealed an absolute requirement for cohesin in hematopoietic stem cell (HSC) function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo, including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose dependency for cohesin in regulating chromatin structure and HSC function.
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Kraft, Bianca, Jan Lombard, Michael Kirsch, Patrick Wuchter, Peter Bugert, Thomas Hielscher, Norbert Blank, and Alwin Kraemer. "Cohesin Subunit SMC3 Levels Impact on Karyotype and Outcome in Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 2786. http://dx.doi.org/10.1182/blood-2018-99-118454.
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Abstract Background: Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disease with highest incidence in the elderly. Advancing age and complex karyotype aberrations, two strong adverse prognostic factors in AML, are closely interconnected and responsible for poor treatment outcome. Chromosomal instability (CIN) is a major contributor to genetic heterogeneity and clonal diversification in AML and its level increases with advancing age both in normal and malignant cells. In elderly healthy individuals clonal mosaicism for chromosomal aberrations in blood cells is associated with an increased risk of a subsequent hematological malignancy. Despite major advances in understanding the genetic landscape of AML and its impact on disease pathophysiology, why genomic integrity declines with age is barely uncovered. For accurate chromosome segregation, sister chromatids are tightly associated until the spindle assembly checkpoint is satisfied, allowing for anaphase‐promoting complex (APC/C)‐mediated anaphase onset. Sister chromatid cohesion is established by the ring‐shaped cohesin complex consisting of four subunits (SMC1A, SMC3, Rad21, and either SA‐1 or SA‐2). Age‐associated CIN in human oocytes seems to be the consequence of cohesin decay with increasing maternal age. Aims and methods: Based on frequent loss‐of‐function mutations in cohesin complex components in human malignancies including AML, we sought to investigate whether decreased cohesin subunit protein levels are associated with aging and leukemogenesis in human individuals by analyzing mononuclear cells (MNCs) from 95 healthy blood donors and 48 AML patients. Results: Western Blot analysis of peripheral blood MNCs from 95 healthy individuals with a median age of 48.5 years (range 19-90) revealed that SMC3 and SMC1A cohesin subunit levels were significantly reduced with advancing age (Fig. 1A). Interestingly, SMC3 protein levels were most prominently reduced in individuals older than 60 years. For SA-1, a borderline significant age-associated decline in protein expression was observed. Surprisingly, compared to healthy donors, Western blot analysis of MNCs from peripheral blood (n=) or bone marrow (n=) from 48 AML patients (median age: 59 years, range 17-91) showed significantly elevated protein expression levels of all cohesin complex components (Fig. 1B). Nevertheless, SMC3 protein levels significantly declined with advancing age in AML patients, similar to the situation in healthy individuals. High SMC3 protein levels were significantly associated with ELN favorable risk group classification (low versus high protein levels, p=0.0010) (Fig. 1C). Moreover, the occurrence of numerical chromosome abnormalities and complex karyotypes increased with decreasing SMC3 protein levels (low versus high protein levels, p=0.0185). The association between age and SMC3 protein levels remained significant after adjusting for karyotype and risk group in multivariate linear regression analysis with age (p=0.03), risk group and numerical karyotype aberrations being independently associated with SMC3 expression (adverse versus favorable risk, p=0.027; numerical aberrations versus normal karyotype, p=0.048). No correlation of SMC3 levels with the mutational status of NPM1 and FLT3 or the CBFB‐MYH11 fusion nor an association of other cohesin subunit expression levels with any of the parameters analyzed was found. Compared to AML patients with lower SMC3 expression, patients with higher levels had a significantly longer overall survival. No survival differences between patients with low versus high expression levels of other cohesin subunits were found. Interestingly, patients with elevated levels of both SMC3 and SA-2 experienced the longest overall survival. Conclusions: In summary, SMC3 cohesin subunit protein levels decline with advancing age in both healthy individuals and AML patients. Reduced SMC3 levels are associated with numerical chromosome abnormalities, complex karyotypes and outcome in AML. These findings are remarkable as overall cohesin mutations are neither associated with karyotype aberrations nor with an impact on survival and possibly explained by the fact that with the exception of SMC3 for all of the other cohesin subunits at least two versions exist, which ‐ at least partially ‐ complement each other. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Heimbruch, Katelyn E., and Sridhar Rao. "Genetic Interactions between Cohesin Mutations and Core-Binding Factor Driver Oncogenes." Blood 134, Supplement_1 (November 13, 2019): 2540. http://dx.doi.org/10.1182/blood-2019-125893.
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Introduction: AML is a genetically heterogeneous disease, with an average 5-year survival of 50%. The core-binding factor complex is essential for normal hematopoiesis and is composed of two subunits, AML1 (aka RUNX1) and CBFB. Both AML1 and CBFB are involved in distinct chromosomal translocations in AML, t(8;21) and inv(16), which generate the fusion oncoproteins AML1-ETO or CBFB-MYH11 (Speck 2002). Heterozygous mutations in one of four members of the cohesin complex (RAD21, SMC3, STAG2, and SMC1A) are commonly found in patients with AML, and frequently (up to 25%) co-occur with AML1-ETO, but never with CBFB-MYH11 (Duployez 2016, Faber 2016). We hypothesize that cohesin mutations synergize with AML1-ETO during leukemic transformation, whereas CBFB-MYH11 and cohesin display a synthetic lethal genetic interaction. Significance: Patients with t(8;21) and inv(16) driven leukemia are treated identically in clinic, having the same prognosis and treatment strategy. Therefore, it is surprising that their co-mutational spectra are quite distinct. Identification of genetic cooperativity and/or synthetic lethality can yield valuable insights into the requisite steps required for AML development, thereby informing potential therapeutic options for these patients. Aims: We aim to determine the mechanism by which CBF driver-oncogenes form distinct genetic interactions with cohesin to promote AML. Methods: We have engineered murine-derived bone marrow cells that express AML1-ETO or CBFB-MYH11 and are either Smc3+/f or Smc3+/-. We have studied the phenotype of these cells in vitro and with next generation sequencing technologies. Results: Our in vitro studies indicate that the loss of cohesin augments the in vitro self-renewal of AML1-ETO, with increased self-renewal compared to AML1-ETO expression alone. By contrast, the introduction of Smc3+/- on the CBFB-MYH11 background reduced serial replating indicating a synthetic lethal interaction between the two. Next, we performed molecular studies to identify the mechanisms underpinning the different phenotypes. First examining the AML1-ETO;Smc3+/- interaction, we performed ATAC-seq. In the AML1-ETO;Smc3+/- background, we have uncovered enrichment of several motifs implicated in myeloid development (RUNX1, GATA2, ERG, PU.1), nuclear architecture (CTCF, CTCFL), and cell proliferation (AP-1, FLI1, JUN). Additionally, RNA-seq reveals downregulation of genes involved in myeloid cell differentiation, changes corresponding to HoxA9 upregulation, and upregulation of the Rb and p53 oncogenic gene signatures in AML1-ETO;Smc3+/- compared to Smc3+/f. Results of our CBFB-MYH11 sequencing studies (RNAseq and ATACseq) are pending. Conclusions: We have identified that Smc3 haploinsufficiency and AML1-ETO cooperate to promote increased self-renewal in vitro while Smc3 haploinsufficiency and CBFB-MYH11 form a synthetic lethal interaction. Smc3 haploinsufficiency and AML1-ETO result in increased chromatin accessibility and transcriptional changes associated with a leukemic signature. Our findings lead us to propose that alteration of cohesin's function as a regulator of chromatin accessibility allows AML1-ETO to bind new sites leading to the transcriptional changes and our observed phenotype. Molecular mechanisms underlying the negative interaction between Smc3 haploinsufficiency and CBFB-MYH11 may be uncovered upon the completion of our NGS studies. Future Directions: We are currently performing animal studies, with both AML1-ETO and CBFB-MYH11 models, to identify an in vivo phenotype. To test our most recent AML1-ETO hypothesis, we plan to perform ChIP-seq to identify changes in genomic AML1-ETO binding sites that occur upon cohesin haploinsufficiency. Analysis of inv(16) NGS experiments expected to be completed within 3 months. Disclosures No relevant conflicts of interest to declare.
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Arkoun, Brahim, Virginie Dufour, Aurélie Siret, Stefania Mazzi, Yasmine Mammasse, Mathieu Vieira, Fabien Boudia, et al. "Modeling Acute Megakaryoblastic Leukemia of Down Syndrome Using Induced Pluripotent Stem Cells." Blood 136, Supplement 1 (November 5, 2020): 1. http://dx.doi.org/10.1182/blood-2020-140986.
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Introduction Development of Acute megakaryoblastic leukemia in Down syndrome children (DS-AMKL) is a multi-step process. Acquired GATA1s mutation during fetal hematopoiesis is responsible of a transient myeloproliferative disorder (TMD) characterized by an accumulation of megakaryoblasts. Although most of TMD regress around birth, some TMD can progress from the initial GATA1s clone to AMKL through the acquisition of additional mutations, including in (i) the cohesin complex (i.e: SMC3), (ii) the JAK/STAT signaling pathway, such as MPL and (iii) the polycomb repressive complex 2 (EZH2). How these mutations cooperate to deregulate megakaryocyte (MK) differentiation and to induce a full-blown AMKL, along with the precise role of trisomy 21 (T21) during this transformation process remain unclear. Because modeling of DS-AMKL is particularly difficult in mice, we performed a step-wise introduction of GATA1s, a gain of function mutation of MPL (MPLW515K) and a heterozygous loss of function mutation in a cohesin (SMC3), separately or in combination, in T21 and isogenic disomic 21 (Dis21) human induced Pluripotent Stem Cells (iPSCs). Methods Trisomy 21 iPSCs were kindly provided by M. Weiss (Memphis, TN). CRISPR/Cas 9 genome editing of GATA1 or SMC3 allowed the generation of GATA1s T21, SMC3+/- T21 and GATA1s SMC3+/- T21 iPSC clones. CRISPR/Cas9-mediated knock-in of MPLW515K was performed in T21 GATA1s iPSCs. The subsequent T21 GATA1sMPLW515K/W515Kclones were selected as well as a revertant Dis21 GATA1sMPLW515K/W515Kclone. Finally, SMC3 insertion/deletion were obtained in isogenic T21 and Dis21 GATA1s MPLW515K/W515K SMC3+/-iPSCs clones. Hematopoietic differentiation was induced in 2D cultures in presence of a matrix and a cocktail of cytokines followed by a MK differentiation with SCF and TPO. MK differentiation was studied by clonogenic assays, flow cytometry, confocal microscopy and ultrastructural studies. Gene expression analyses were performed by RNA-seq on highly purified MK from all genotypes. Results GATA1s alone blocked MK maturation characterized by a persistent CD34 expression, an accumulation of abnormal large granules, a defect in the development of demarcation membranes (DMS), and a marked decrease in proplatelet formation. The typical GATA1s MK were large megakaryoblasts with numerous large granules and rare DMS. However, GATA1s alone had no effect on the clonogenic activity in CFU-MK assays and MK numbers. The introduction of the MPLW515K mutation did not modify this phenotype either in Dis21 or T21 GATA1s MK, but induced a complete TPO independence. SMC3+/- alone enhanced the MK maturation allowing the generation of a higher number of proplatelets-generating MK. Importantly, the combination of GATA1s and SMC3+/- mutations had a marked cooperative effect that worsened the MK maturation defect, led to the generation of abnormal megakaryoblasts with only a pre-DMS and resulted in enhanced proliferation and ploidization both in Dis21 and T21 iPSCs. Interestingly, the proliferation was markedly higher in T21 clones compared to Dis21 counterparts. RNA-seq and GSEA analyses showed that T21 GATA1s SMC3+/- mutant MK exhibited transcriptional signatures consistent with a dramatic decrease in the expression of maturation genes, including GATA1 target genes, while DNA replication gene markers were increased compared with GATA1s alone. T21 GATA1s MPLW515K/W515K SMC3+/- MK were enriched for AMKL signatures as compared to isogenic Dis21 GATA1sMPLW515K/W515K SMC3+/- MK. Ongoing ATAC-seq analyses will define the consequence of the different mutations on chromatin accessibility. Conclusion Using iPSC modeling, we analyzed in a human cell-context the consequences of the different combination of mutations associated with DS-AMKL that would be difficult to model using human primary cells. Our data demonstrate that GATA1s expression cooperates with SMC3+/- to enhance proliferation of megakaryoblasts from T21 iPSCs and isogenic Dis21 iPSCs hence reproducing the abnormalities observed in DS-AMKL. T21 is not directly involved in the MK differentiation defects but rather give a proliferative advantage supporting its role in leukemia development. Disclosures No relevant conflicts of interest to declare.
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Kurze, Alexander, Katharine A. Michie, Sarah E. Dixon, Ajay Mishra, Takehiko Itoh, Syma Khalid, Lana Strmecki, et al. "A positively charged channel within the Smc1/Smc3 hinge required for sister chromatid cohesion." EMBO Journal 30, no. 2 (December 7, 2010): 364–78. http://dx.doi.org/10.1038/emboj.2010.315.
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Meyer, Alison E., Cary Stelloh, Kirthi Pulakanti, Robert Burns, Joseph B. Fisher, Katelyn E. Heimbruch, Sergey Tarima, Aaron D. Viny, George S. Vassiliou, and Sridhar Rao. "Combinatorial Genetic Uncovers DOCK1/RAC2 As Specific Targets for the Treatment of NPM1;Cohesin Mutated AML." Blood 138, Supplement 1 (November 5, 2021): 3288. http://dx.doi.org/10.1182/blood-2021-148811.
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Abstract Acute myeloid leukemia (AML) is an aggressive malignancy of the blood and bone marrow resulting from the accumulation of multiple serially acquired mutations. The mutational complexity of the disease makes AML difficult to treat, contributing to a low 5-year survival rate. A better understanding of how different mutations interact with one another to influence disease characteristics is critical and may result in the development of targeted therapies to improve patient outcome. The most common recurrent somatic mutation in AML affects the gene NPM1 and occurs in 25-30% of patients. This mutation results in the aberrant cytoplasmic localization of the protein and is termed NPM1cA (Falini et al. 2005, Cancer Genome Atlas Research Network 2013). NPM1cA is considered to be a driver of AML, however Npm1 cA/+ mice only develop disease after a long latency (median 18 months), suggesting that other cooperating mutations are required for AML development (Vassiliou et al. 2011). Approximately 50% of patients with an NPM1cA mutation also harbor a mutation in one of four members of the cohesin complex (STAG2, SMC3, SMC1A, and RAD21). Mutations in cohesin genes are mutually exclusive and result in haploinsufficiency of the complex. As cohesin is known to regulate gene expression by facilitating promoter-enhancer interactions and three-dimensional genome organization, we wished to determine how cohesin mutation influences AML biology and gene expression in the presence of NPM1cA. We utilized the inducible Npm1 cAflox/+ and Smc3 flox/+ mouse models to examine this genetic interaction. We and others have shown that cohesin mutations result in enhanced hematopoietic stem and progenitor cell (HSPC) self-renewal (Mazumdar et al. 2015, Viny et al. 2015, Mullenders et al. 2015, Galeev et al. 2016, Fisher et al. 2017). Consistent with this, Npm1 cA/+;Smc3 Δ/+ HSPCs show enhanced self-renewal in vitro over HSPCs harboring either single mutation. Despite a shared role in self-renewal, Npm1 cA/+;Smc3 Δ/+mice developed AML with similar latency as Npm1 cA/+ mice. Interestingly, however, Npm1 cA/+;Smc3 Δ/+ HSPCs exhibited dysregulation of a unique set of genes compared to cells from either single mutant, suggesting that the Npm1 cA;cohesin mutational combination uniquely alters the transcriptional environment. Further, Npm1 cA/+;Smc3 Δ/+ leukemias had a completely unique spectrum of acquired mutations compared to Npm1 cA/+ leukemias, suggesting that the addition of Smc3 haploinsufficiency to Npm1 cA/+alters AML evolution and that different driver mutations result in the accumulation of very different somatic mutations. Among the uniquely upregulated genes in Npm1 cA/+;Smc3 Δ/+ HSPCs is Dock1, a guanine nucleotide exchange factor (GEF) for Rac1/2. As high Dock1 expression has been associated with low overall and disease-free survival in multiple cohorts of AML patients (Lee et al. 2017, Zhang et al. 2019), we hypothesized that Dock1 would be a novel target for the treatment of Npm1cA; cohesin mut leukemias. Consistent with this hypothesis, We found that knockdown of Dock1 resulted in decreased growth and adhesion and increased apoptosis in an Npm1 cA/+;Smc3 Δ/+leukemic line, but not in an Npm1 cAsingle mutant line. Higher Rac activity was also observed in Npm1 cA/+;Smc3 Δ/+ vs. Npm1 cA/+ leukemic lines. We found that DN Rac2 specifically impacted both the growth and apoptosis of an Npm1 cA/+;Smc3 Δ/+line, suggesting that Dock1 functions primarily through Rac2 to regulate survival. Importantly, the Dock1/Rac pathway is specifically targetable in Npm1 cA/+;Smc3 Δ/+ AMLs in vitro and in vivo, as knockdown of Dock1 resulted in prolonged latency in a Npm1 cA/+;Smc3 Δ/+ transplant model and slowed the growth and enhanced apoptosis of an Npm1 cA/+;Smc3 Δ/+, but not an Npm1 cA/+, leukemic line. Further, small molecule inhibitors of Dock and Rac had similar effects. Our results suggest that Dock1/Rac2 represent unique targets for the treatment of patients harboring the NPM1cA;cohesin mutational combination and provide validity to the concept that combinatorial genetics can uncover novel precision oncology targets. Disclosures Vassiliou: Kymab Ltd: Divested equity in a private or publicly-traded company in the past 24 months; STRM.BIO: Consultancy; Astrazeneca: Consultancy.
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Fujita, Yuki, Koji Masuda, Masashige Bando, Ryuichiro Nakato, Yuki Katou, Takashi Tanaka, Masahiro Nakayama, et al. "Decreased cohesin in the brain leads to defective synapse development and anxiety-related behavior." Journal of Experimental Medicine 214, no. 5 (April 13, 2017): 1431–52. http://dx.doi.org/10.1084/jem.20161517.
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Abnormal epigenetic regulation can cause the nervous system to develop abnormally. Here, we sought to understand the mechanism by which this occurs by investigating the protein complex cohesin, which is considered to regulate gene expression and, when defective, is associated with higher-level brain dysfunction and the developmental disorder Cornelia de Lange syndrome (CdLS). We generated conditional Smc3-knockout mice and observed greater dendritic complexity and larger numbers of immature synapses in the cerebral cortex of Smc3+/− mice. Smc3+/− mice also exhibited more anxiety-related behavior, which is a symptom of CdLS. Further, a gene ontology analysis after RNA-sequencing suggested the enrichment of immune processes, particularly the response to interferons, in the Smc3+/− mice. Indeed, fewer synapses formed in their cortical neurons, and this phenotype was rescued by STAT1 knockdown. Thus, low levels of cohesin expression in the developing brain lead to changes in gene expression that in turn lead to a specific and abnormal neuronal and behavioral phenotype.
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Ghiselli, Giancarlo, and Renato V. Iozzo. "Overexpression of Bamacan/SMC3 Causes Transformation." Journal of Biological Chemistry 275, no. 27 (May 3, 2000): 20235–38. http://dx.doi.org/10.1074/jbc.c000213200.
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Milanovich, Samuel, Jonathan Peterson, and Sridhar Rao. "Cohesin Complex Plays Distinct Roles in Normal Versus Malignant Hematopoiesis." Blood 124, no. 21 (December 6, 2014): 3556. http://dx.doi.org/10.1182/blood.v124.21.3556.3556.
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Abstract The advent of next generation sequencing and emerging data demonstrating epigenetic dysregulation in cancer have greatly improved our understanding of common pathways underlying leukemogenesis in AML. Recent genomic studies have identified recurrent somatic mutations in cohesin complex genes in up to 13% of AML patients. The canonical role of the cohesin complex is to facilitate symmetrical DNA segregation of sister chromatids during mitosis, yet aneuploidy is an uncommon finding in AML. Thus the mechanisms by which cohesin mutations contribute to leukemogenesis in AML remain unknown. Here we investigate the role of the cohesin complex genes Scc1 and Smc3 in MLL-AF9 and AML1-ETO murine models of leukemia. Most cohesin complex mutations in AML are predicted to be loss of function mutations leading to somatic haplo-insufficiency. To model haplo-insufficiency of cohesin genes we utilized lentiviral RNA interference targeted against Scc1 and Smc3 in wild type lineage-negative (Lin-) bone marrow or Lin- bone marrow transduced with MLL-AF9 or AML1-ETO. MLL-AF9 and AML1-ETO transduced Lin- bone marrow form tumor sphere-like colonies and demonstrate enhanced self-renewal and proliferation in vitro. Knockdown of Scc1 or Smc3 in Lin- bone marrow, MLL-AF9, and AML1-ETO transduced bone marrow was confirmed by real time quantitative PCR (RT-qPCR). Following knockdown of Scc1 or Smc3, MLL-AF9 transduced cells demonstrate diminished colony-forming capacity and fold cellular expansion in vitro compared to cells infected with empty vector (p-value <0.05, Figure 1). In AML1-ETO there was a trend towards fewer colony forming units following knockdown of Scc1 and Smc3 that was not statistically significant (p-value 0.36, 0.27, respectively, Figure 1A). However there was a more substantial block in the proliferative capacity of AML1-ETO cells following knockdown of Scc1 or Smc3 (p-value 0.006, 0.07, respectively, Figure 1B). Conversely, no change in colony formation or proliferation was seen in Lin- bone marrow following knockdown of Scc1 (Figure 1A), while knockdown of Smc3 was associated with a trend towards decreased colony formation (p-value 0.08) and decreased proliferation (p-value<0.01, Figure 1B). Due to cohesin’s canonical function in DNA segregation we investigated whether the observed findings were simply due to mitotic defects secondary to disruption of the cohesin complex. Propidium iodide staining was performed to assess cell-cycle phase in MLL-AF9 transduced cells and did not demonstrate an increase in aneuploidy following Scc1 or Smc3 knockdown. Collectively, these data show that knockdown of cohesin subunits Scc1 or Smc3 have distinct differences between normal and malignant hematopoiesis. These differences depend upon the state of the cell transduced (Lin- bone marrow, MLL-AF9 or AML1-ETO) and which individual cohesin subunit is involved (Scc1 or Smc3). MLL-AF9 colony formation and proliferation were highly dependent upon intact Scc1 and Smc3. Whereas in AML1-ETO, colony formation was less affected by cohesin knockdown, but proliferation was impaired. In Lin- bone marrow, colony formation and proliferation were impaired by Smc3 knockdown, while self-renewal and proliferation were unchanged after knockdown of Scc1. The mechanism of impairment does not appear to be failure of mitosis resulting in aneuploidy and subsequent apoptosis. This suggests that the role of the cohesin complex in AML is dependent upon the underlying leukemogenic driver mutation, the specific cohesin subunit gene involved, and is unique from its role in normal hematopoiesis. Future studies will need to explore the specific pathways and interactions by which cohesin mutations contribute to malignant hematopoiesis. Figure 2 Analysis of in vitro colony formation and proliferation after cohesin knockdown in Lin- bone marrow, MLL-AF9, and AML1-ETO. Figure 2. Analysis of in vitro colony formation and proliferation after cohesin knockdown in Lin- bone marrow, MLL-AF9, and AML1-ETO. Disclosures No relevant conflicts of interest to declare.
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Wang, Ning, Yanan Zhu, Min Xie, Lintao Wang, Feiyan Jin, Yihui Li, Qingxin Yuan, and Wei De. "Long Noncoding RNA Meg3 Regulates Mafa Expression in Mouse Beta Cells by Inactivating Rad21, Smc3 or Sin3α." Cellular Physiology and Biochemistry 45, no. 5 (2018): 2031–43. http://dx.doi.org/10.1159/000487983.
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Background/Aims: The main pathogenic mechanism of diabetes is a decrease in the number of islet beta cells or a decline in their function. Recent studies have shown that pancreatic long noncoding RNAs (lncRNAs) have a high degree of tissue specificity and may be involved in the maintenance of islet cells function and the development of diabetes. The aim of this study was to investigate the molecular regulatory mechanism of mouse maternal expressed gene 3 (Meg3) in insulin biosynthesis in pancreatic islets. Methods: Chromatin immunoprecipitation–quantitative polymerase chain reaction (qPCR) and RNA immunoprecipitation–qPCR were used to investigate the molecular mechanism of lncRNA Meg3 in insulin biosynthesis by regulating v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), a mature beta cell marker in the MIN6 beta cell line. Further, the expression levels of Meg3, Ezh2, MafA, Rad21, Smc3, and Sin3α were analyzed in vivo and in vitro by RT-PCR and western blotting. Results: Intranuclear lncRNA Meg3 can bind EZH2, a methyltransferase belonging to the Polycomb repressive complex-2, in pancreatic islet cells. In addition, knockdown of Ezh2 can also inhibit the expression of MafA and Ins2, while expression levels of Rad21, Smc3, and Sin3α are upregulated, by interfering with Ezh2 or Meg3 in pancreatic beta cells. Knockdown of Meg3 resulted in the loss of EZH2 binding and H3K27 trimethylation occupancy of Rad21, Smc3, and Sin3α promoter regions. The inhibition of Rad21, Smc3, or Sin3α, which directly act on the MafA promoter, leads to upregulated expression of MafA in both MIN6 cells and mouse islets. Moreover, the synthesis and secretion of insulin were increased by inhibition of these transcription factors. Conclusions: Pancreatic lncRNA Meg3 can epigenetically regulate the expression of Rad21, Smc3, and Sin3α via EZH2-driven H3K27 methylation. By inhibiting the expression of Rad21, Smc3, or Sin3α, Meg3 promotes the expression of MafA and affects the production of insulin.
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Lam, W. S. "Characterization of Arabidopsis thaliana SMC1 and SMC3: evidence that AtSMC3 may function beyond chromosome cohesion." Journal of Cell Science 118, no. 14 (July 15, 2005): 3037–48. http://dx.doi.org/10.1242/jcs.02443.
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Alomer, Reem M., Eulália M. L. da Silva, Jingrong Chen, Katarzyna M. Piekarz, Katherine McDonald, Courtney G. Sansam, Christopher L. Sansam, and Susannah Rankin. "Esco1 and Esco2 regulate distinct cohesin functions during cell cycle progression." Proceedings of the National Academy of Sciences 114, no. 37 (August 28, 2017): 9906–11. http://dx.doi.org/10.1073/pnas.1708291114.
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Sister chromatids are tethered together by the cohesin complex from the time they are made until their separation at anaphase. The ability of cohesin to tether sister chromatids together depends on acetylation of its Smc3 subunit by members of the Eco1 family of cohesin acetyltransferases. Vertebrates express two orthologs of Eco1, called Esco1 and Esco2, both of which are capable of modifying Smc3, but their relative contributions to sister chromatid cohesion are unknown. We therefore set out to determine the precise contributions of Esco1 and Esco2 to cohesion in vertebrate cells. Here we show that cohesion establishment is critically dependent upon Esco2. Although most Smc3 acetylation is Esco1 dependent, inactivation of the ESCO1 gene has little effect on mitotic cohesion. The unique ability of Esco2 to promote cohesion is mediated by sequences in the N terminus of the protein. We propose that Esco1-dependent modification of Smc3 regulates almost exclusively the noncohesive activities of cohesin, such as DNA repair, transcriptional control, chromosome loop formation, and/or stabilization. Collectively, our data indicate that Esco1 and Esco2 contribute to distinct and separable activities of cohesin in vertebrate cells.
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Eijpe, Maureen, Hildo Offenberg, Rolf Jessberger, Ekaterina Revenkova, and Christa Heyting. "Meiotic cohesin REC8 marks the axial elements of rat synaptonemal complexes before cohesins SMC1β and SMC3." Journal of Cell Biology 160, no. 5 (March 3, 2003): 657–70. http://dx.doi.org/10.1083/jcb.200212080.
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In meiotic prophase, the sister chromatids of each chromosome develop a common axial element (AE) that is integrated into the synaptonemal complex (SC). We analyzed the incorporation of sister chromatid cohesion proteins (cohesins) and other AE components into AEs. Meiotic cohesin REC8 appeared shortly before premeiotic S phase in the nucleus and formed AE-like structures (REC8-AEs) from premeiotic S phase on. Subsequently, meiotic cohesin SMC1β, cohesin SMC3, and AE proteins SCP2 and SCP3 formed dots along REC8-AEs, which extended and fused until they lined REC8-AEs along their length. In metaphase I, SMC1β, SMC3, SCP2, and SCP3 disappeared from the chromosome arms and accumulated around the centromeres, where they stayed until anaphase II. In striking contrast, REC8 persisted along the chromosome arms until anaphase I and near the centromeres until anaphase II. We propose that REC8 provides a basis for AE formation and that the first steps in AE assembly do not require SMC1β, SMC3, SCP2, and SCP3. Furthermore, SMC1β, SMC3, SCP2, and SCP3 cannot provide arm cohesion during metaphase I. We propose that REC8 then provides cohesion. RAD51 and/or DMC1 coimmunoprecipitates with REC8, suggesting that REC8 may also provide a basis for assembly of recombination complexes.
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Almeida, Bruno Rafael Ribeiro de, Renata Coelho Rodrigues Noronha, Cleusa Yoshiko Nagamachi, and Júlio Cesar Pieczarka. "Marcadores protéicos de sinapse e dinâmica de quebras de DNA programadas em meiose aquiasmática do Escorpião T. silvestris (Scorpiones: Buthidae)." Semina: Ciências Biológicas e da Saúde 38, no. 1supl (February 16, 2018): 205. http://dx.doi.org/10.5433/1679-0367.2017v38n1suplp205.
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Análises meióticas realizadas em escorpiões Buthidae, por microscopia óptica e eletrônica, demonstraram bivalentes holocinéticos, heterosinápticos e com ausência de quiasmas e nódulos de recombinação durante a meiose do macho. No presente estudo analisamos o mecanismo sináptico e a dinâmica de quebras programadas de cadeias de DNA na meiose do butídeo Tityus silvestris por imunofluorescência. Preparações meióticas fixadas em paraformaldeído 2%, foram submetidas à imunodetecção com anticorpos primários anti-SMC3 e anti-?H2AX, bem como Imuno-FISH com sonda telomérica de artrópodes (TTAGG) e anti-SMC3. Nossos resultados demonstraram que o cariótipo de Tityus silvestris apresenta 2n = 24, com morfologia holocêntrica e ausência de cromossomos sexuais heteromórficos. Imuno-FISH com sonda telomérica e anti-SMC3 (que detecta eixos axiais/laterais do complexo sinaptonêmico) permitiu analisar a progressão da sinapse neste escorpião: em leptóteno, a coesina SMC3 apresenta-se na forma de pontuações e curtos filamentos; no início do zigóteno, cromossomos são organizados em configuração bouquet, e a sinapse inicia-se a partir das regiões teloméricas; em paquítenos iniciais, gaps foram observados ao longo de alguns complexos sinaptonêmicos; em paquítenos tardios, a sinapse completa-se, permitindo individualizar os 12 bivalentes; finalmente, em células pós-paquitênicas, o eixo SMC3 localiza-se centralmente ao longo de cada bivalente até Metáfase I. Em relação aos eventos iniciais do processo de recombinação, quebras de cadeias duplas de DNA (evidenciadas por ?H2AX) iniciam-se em núcleos pré-leptóteno. A variante histônica ?H2AX é localizada sobre eixo SMC3, distribuindo-se de acordo com o avanço da sinapse em zigóteno e desaparecendo no final do Paquíteno. Nossos resultados mostraram que na meiose de T. silvestris, formação de quebras programadas de DNA ocorrem antes do início da sinapse, diferindo do padrão observado em Drosophila melanogaster e C. elegans. A ocorrência de ?H2AX durante a meiose aquiasmática deste escorpião sugere que quebras de cadeia dupla de DNA durante a prófase I, sejam reperadas por um mecanismo distinto ao da recombinação homóloga. Finalmente, apesar da aparente ausência de recombinação, o reparo de quebras de DNA programadas é necessário para o progresso normal da meiose em T. silvestris.
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Khanna, Hemant, Toby W. Hurd, Concepcion Lillo, Xinhua Shu, Sunil K. Parapuram, Shirley He, Masayuki Akimoto, et al. "RPGR-ORF15, Which Is Mutated in Retinitis Pigmentosa, Associates with SMC1, SMC3, and Microtubule Transport Proteins." Journal of Biological Chemistry 280, no. 39 (July 25, 2005): 33580–87. http://dx.doi.org/10.1074/jbc.m505827200.
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Noronha, Renata Coelho Rodrigues, Bruno Rafael Ribeiro de Almeida, Marlyson Jeremias Rodrigues da Costa, Cleusa Yoshiko Nagamachi, and Julio Cesar Pieczarka. "Synaptic behavior of Leptodactylus pentadactylus (Anura: Leptodactylidae) by immunolocalization of proteins." Semina: Ciências Biológicas e da Saúde 38, no. 1supl (February 16, 2018): 242. http://dx.doi.org/10.5433/1679-0367.2017v38n1suplp242.
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Most species of the genus Leptodactylus share similar karyotypes, with 2n=22 and NF=44. The species L. pentadactylus presents a multivalent in its karyotype, resulting from multiple translocations, forming a ring chromosome during meiosis I. In this study analyzed the meiotic behavior of L. pentadactylus, from Brazilian Amazonia, through immunoprotein markers. Testicular tissues of an adult male were collected and analyzed by immunofluorescence microscopy, using antibodies to detect the following meiotic proteins: SMC3, component of chromosomal axis, and responsible for cohesion between sister chromatids; ?-H2AX in a protein marker of meiotic silencing of unsynapsed chromatin (MSUC). The results showed that: in leptotene, SMC3 and ?-H2AX mark fuzzy segments throughout all the chromatin; in the zygotene; regions that start synapses are intensely marked by ?-H2AX; in turn, with the advancement of the synapse at the end of the zygotene, ?-H2AX markings expand evenly in the chromatin; in pachytene, the synapsis remains incomplete, and several asynaptic regions were noted, with ?-H2AX markings more intense on synapsed regions of chromosomes involved or not in multivalent links; in diplotene, the synaptonemal complex is disorganized, SMC3 cohesin is present on partially decondensed, chromatin, and ?-H2AX markings are present only in some regions; in diakinesis, SMC3 maintains the same pattern of diplotene, however, ?-H2AX markings are quite reduced. The results of meiotic behavior of L. pentadactylus show asynaptic axes in pachytene, which probably do not present homology with each other, corresponding to segments that suffered multiple rearrangements. SMC3 pattern and reduction of ?-H2AX markings in diplotene, suggest decondensation of chromatin, with reactivation of transcription in chromosomal handles. The absence of ?-H2AX markings in diakinesis show that the rearranged chromosomes of L. pentadactylus do not compromise the spermatogenesis of the animal, ensuring its meiotic dynamic and fertility.
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Ampatzidou, Eleni, Anja Irmisch, Matthew J. O'Connell, and Johanne M. Murray. "Smc5/6 Is Required for Repair at Collapsed Replication Forks." Molecular and Cellular Biology 26, no. 24 (October 9, 2006): 9387–401. http://dx.doi.org/10.1128/mcb.01335-06.
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ABSTRACT In eukaryotes, three pairs of structural-maintenance-of-chromosome (SMC) proteins are found in conserved multisubunit protein complexes required for chromosomal organization. Cohesin, the Smc1/3 complex, mediates sister chromatid cohesion while two condensin complexes containing Smc2/4 facilitate chromosome condensation. Smc5/6 scaffolds an essential complex required for homologous recombination repair. We have examined the response of smc6 mutants to the inhibition of DNA replication. We define homologous recombination-dependent and -independent functions for Smc6 during replication inhibition and provide evidence for a Rad60-independent function within S phase, in addition to a Rad60-dependent function following S phase. Both genetic and physical data show that when forks collapse (i.e., are not stabilized by the Cds1Chk2 checkpoint), Smc6 is required for the effective repair of resulting lesions but not for the recruitment of recombination proteins. We further demonstrate that when the Rad60-dependent, post-S-phase Smc6 function is compromised, the resulting recombination-dependent DNA intermediates that accumulate following release from replication arrest are not recognized by the G2/M checkpoint.
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Iłkiewicz, K., J. Mikołajewska, and K. Belczyński. "SMC3 As a Test To The Binary Evolution." EAS Publications Series 71-72 (2015): 155–58. http://dx.doi.org/10.1051/eas/1571034.
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Robison, Brett, Vincent Guacci, and Douglas Koshland. "A role for the Smc3 hinge domain in the maintenance of sister chromatid cohesion." Molecular Biology of the Cell 29, no. 3 (February 2018): 339–55. http://dx.doi.org/10.1091/mbc.e17-08-0511.
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Tao, Hirotaka, Jean-Philippe Lambert, Theodora M. Yung, Min Zhu, Noah A. Hahn, Danyi Li, Kimberly Lau, et al. "IRX3/5 regulate mitotic chromatid segregation and limb bud shape." Development 147, no. 19 (September 9, 2020): dev180042. http://dx.doi.org/10.1242/dev.180042.
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ABSTRACTPattern formation is influenced by transcriptional regulation as well as by morphogenetic mechanisms that shape organ primordia, although factors that link these processes remain under-appreciated. Here we show that, apart from their established transcriptional roles in pattern formation, IRX3/5 help to shape the limb bud primordium by promoting the separation and intercalation of dividing mesodermal cells. Surprisingly, IRX3/5 are required for appropriate cell cycle progression and chromatid segregation during mitosis, possibly in a nontranscriptional manner. IRX3/5 associate with, promote the abundance of, and share overlapping functions with co-regulators of cell division such as the cohesin subunits SMC1, SMC3, NIPBL and CUX1. The findings imply that IRX3/5 coordinate early limb bud morphogenesis with skeletal pattern formation.
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Borges, Vanessa, Chris Lehane, Lidia Lopez-Serra, Helen Flynn, Mark Skehel, Tom Rolef Ben-Shahar, and Frank Uhlmann. "Hos1 Deacetylates Smc3 to Close the Cohesin Acetylation Cycle." Molecular Cell 39, no. 5 (September 2010): 677–88. http://dx.doi.org/10.1016/j.molcel.2010.08.009.
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Wang, Dongchang, Lifei Wang, Yu Zhang, Yunxia Zhao, and Gang Chen. "Hydrogen gas inhibits lung cancer progression through targeting SMC3." Biomedicine & Pharmacotherapy 104 (August 2018): 788–97. http://dx.doi.org/10.1016/j.biopha.2018.05.055.
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Wang, Tianjiao, Brandi Glover, Gayla Hadwiger, Christopher A. Miller, Orsola di Martino, and John S. Welch. "Smc3 is required for mouse embryonic and adult hematopoiesis." Experimental Hematology 70 (February 2019): 70–84. http://dx.doi.org/10.1016/j.exphem.2018.11.008.
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Stursberg, S., B. Riwar, and R. Jessberger. "Cloning and characterization of mammalian SMC1 and SMC3 genes and proteins, components of the DNA recombination complexes RC-1." Gene 228, no. 1-2 (March 1999): 1–12. http://dx.doi.org/10.1016/s0378-1119(99)00021-9.
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Cheng, Qi, Wanjie Huang, Ning Chen, Yunxiao Shang, and Han Zhang. "SMC3 may play an important role in atopic asthma development." Clinical Respiratory Journal 10, no. 4 (January 15, 2015): 469–76. http://dx.doi.org/10.1111/crj.12247.
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Rowland, Benjamin D., Maurici B. Roig, Tatsuya Nishino, Alexander Kurze, Pelin Uluocak, Ajay Mishra, Frédéric Beckouët, et al. "Building Sister Chromatid Cohesion: Smc3 Acetylation Counteracts an Antiestablishment Activity." Molecular Cell 33, no. 6 (March 2009): 763–74. http://dx.doi.org/10.1016/j.molcel.2009.02.028.
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Zhang, Nenggang, Sergey G. Kuznetsov, Shyam K. Sharan, Kaiyi Li, Pulivarthi H. Rao, and Debananda Pati. "A handcuff model for the cohesin complex." Journal of Cell Biology 183, no. 6 (December 15, 2008): 1019–31. http://dx.doi.org/10.1083/jcb.200801157.
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The cohesin complex is responsible for the accurate separation of sister chromatids into two daughter cells. Several models for the cohesin complex have been proposed, but the one-ring embrace model currently predominates the field. However, the static configuration of the embrace model is not flexible enough for cohesins to perform their functions during DNA replication, transcription, and DNA repair. We used coimmunoprecipitation, a protein fragment complement assay, and a yeast two-hybrid assay to analyze the protein–protein interactions among cohesin subunits. The results show that three of the four human cohesin core subunits (Smc1, Smc3, and Rad21) interact with themselves in an Scc3 (SA1/SA2)-dependent manner. These data support a two-ring handcuff model for the cohesin complex, which is flexible enough to establish and maintain sister chromatid cohesion as well as ensure the fidelity of chromosome segregation in higher eukaryotes.
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Canudas, Silvia, and Susan Smith. "Differential regulation of telomere and centromere cohesion by the Scc3 homologues SA1 and SA2, respectively, in human cells." Journal of Cell Biology 187, no. 2 (October 12, 2009): 165–73. http://dx.doi.org/10.1083/jcb.200903096.
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Replicated sister chromatids are held together until mitosis by cohesin, a conserved multisubunit complex comprised of Smc1, Smc3, Scc1, and Scc3, which in vertebrate cells exists as two closely related homologues (SA1 and SA2). Here, we show that cohesinSA1 and cohesinSA2 are differentially required for telomere and centromere cohesion, respectively. Cells deficient in SA1 are unable to establish or maintain cohesion between sister telomeres after DNA replication in S phase. The same phenotype is observed upon depletion of the telomeric protein TIN2. In contrast, in SA2-depleted cells telomere cohesion is normal, but centromere cohesion is prematurely lost. We demonstrate that loss of telomere cohesion has dramatic consequences on chromosome morphology and function. In the absence of sister telomere cohesion, cells are unable to repair chromatid breaks and suffer sister telomere loss. Our studies elucidate the functional distinction between the Scc3 homologues in human cells and further reveal an essential role for sister telomere cohesion in genomic integrity.
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Stephens, Andrew D., Julian Haase, Leandra Vicci, Russell M. Taylor, and Kerry Bloom. "Cohesin, condensin, and the intramolecular centromere loop together generate the mitotic chromatin spring." Journal of Cell Biology 193, no. 7 (June 27, 2011): 1167–80. http://dx.doi.org/10.1083/jcb.201103138.
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Sister chromatid cohesion provides the mechanistic basis, together with spindle microtubules, for generating tension between bioriented chromosomes in metaphase. Pericentric chromatin forms an intramolecular loop that protrudes bidirectionally from the sister chromatid axis. The centromere lies on the surface of the chromosome at the apex of each loop. The cohesin and condensin structural maintenance of chromosomes (SMC) protein complexes are concentrated within the pericentric chromatin, but whether they contribute to tension-generating mechanisms is not known. To understand how pericentric chromatin is packaged and resists tension, we map the position of cohesin (SMC3), condensin (SMC4), and pericentric LacO arrays within the spindle. Condensin lies proximal to the spindle axis and is responsible for axial compaction of pericentric chromatin. Cohesin is radially displaced from the spindle axis and confines pericentric chromatin. Pericentric cohesin and condensin contribute to spindle length regulation and dynamics in metaphase. Together with the intramolecular centromere loop, these SMC complexes constitute a molecular spring that balances spindle microtubule force in metaphase.
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Ladurner, Rene, Venugopal Bhaskara, Pim J. Huis in ’t Veld, Iain F. Davidson, Emanuel Kreidl, Georg Petzold, and Jan-Michael Peters. "Cohesin’s ATPase Activity Couples Cohesin Loading onto DNA with Smc3 Acetylation." Current Biology 24, no. 19 (October 2014): 2228–37. http://dx.doi.org/10.1016/j.cub.2014.08.011.
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Xiong, Bo, Shuai Lu, and Jennifer L. Gerton. "Hos1 Is a Lysine Deacetylase for the Smc3 Subunit of Cohesin." Current Biology 20, no. 18 (September 2010): 1660–65. http://dx.doi.org/10.1016/j.cub.2010.08.019.
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Patel, Chirag A., and Giancarlo Ghiselli. "The RET finger protein interacts with the hinge region of SMC3." Biochemical and Biophysical Research Communications 330, no. 1 (April 2005): 333–40. http://dx.doi.org/10.1016/j.bbrc.2005.02.162.
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Gregson, Heather C., John A. Schmiesing, Jong-Soo Kim, Toshiki Kobayashi, Sharleen Zhou, and Kyoko Yokomori. "A Potential Role for Human Cohesin in Mitotic Spindle Aster Assembly." Journal of Biological Chemistry 276, no. 50 (October 4, 2001): 47575–82. http://dx.doi.org/10.1074/jbc.m103364200.
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The cohesin multiprotein complex containing SMC1, SMC3, Scc3 (SA), and Scc1 (Rad21) is required for sister chromatid cohesion in eukaryotes. Although metazoan cohesin associates with chromosomes and was shown to function in the establishment of sister chromatid cohesion during interphase, the majority of cohesin was found to be off chromosomes and reside in the cytoplasm in metaphase. Despite its dissociation from chromosomes, however, microinjection of an antibody against human SMC1 led to disorganization of the metaphase plate and cell cycle arrest, indicating that human cohesin still plays an important role in metaphase. To address the mitotic function of human cohesin, the subcellular localization of cohesin components was reexamined in human cells. Interestingly, we found that cohesin localizes to the spindle poles during mitosis and interacts with NuMA, a spindle pole-associated factor required for mitotic spindle organization. The interaction with NuMA persists during interphase. Similar to NuMA, a significant amount of cohesin was found to associate with the nuclear matrix. Furthermore, in the absence of cohesin, mitotic spindle asters failed to formin vitro. Our results raise the intriguing possibility that in addition to its well demonstrated function in sister chromatid cohesion, cohesin may be involved in spindle assembly during mitosis.
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Rahman, Sadia, Mathew J. K. Jones, and Prasad V. Jallepalli. "Cohesin recruits the Esco1 acetyltransferase genome wide to repress transcription and promote cohesion in somatic cells." Proceedings of the National Academy of Sciences 112, no. 36 (August 24, 2015): 11270–75. http://dx.doi.org/10.1073/pnas.1505323112.
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The cohesin complex links DNA molecules and plays key roles in the organization, expression, repair, and segregation of eukaryotic genomes. In vertebrates the Esco1 and Esco2 acetyltransferases both modify cohesin’s Smc3 subunit to establish sister chromatid cohesion during S phase, but differ in their N-terminal domains and expression during development and across the cell cycle. Here we show that Esco1 and Esco2 also differ dramatically in their interaction with chromatin, as Esco1 is recruited by cohesin to over 11,000 sites, whereas Esco2 is infrequently enriched at REST/NRSF target genes. Esco1’s colocalization with cohesin occurs throughout the cell cycle and depends on two short motifs (the A-box and B-box) present in and unique to all Esco1 orthologs. Deleting either motif led to the derepression of Esco1-proximal genes and functional uncoupling of cohesion from Smc3 acetylation. In contrast, other mutations that preserved Esco1’s recruitment separated its roles in cohesion establishment and gene silencing. We conclude that Esco1 uses cohesin as both a substrate and a scaffold for coordinating multiple chromatin-based transactions in somatic cells.
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Shiba, Norio, Kenichi Yoshida, Yasunobu Nagata, Ayana Kon, Yusuke Okuno, Yuichi Shiraishi, Motohiro Kato, et al. "Whole-Exome Resequencing Identifies Somatic Mutations Of BCOR and BCORL1 Transcriptional Corepressor Genes and Major Cohesin Complex Component Genes In Pediatric Acute Myeloid Leukemia." Blood 122, no. 21 (November 15, 2013): 834. http://dx.doi.org/10.1182/blood.v122.21.834.834.
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Abstract Background Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease. Currently, targeted sequencing efforts have identified several mutations that carry diagnostic and prognostic information such as RAS, KIT, and FLT3 in both adult and pediatric AML, and NPM1 and TET2 in adult AML. Meanwhile, the recent development of massively parallel sequencing technologies has provided a new opportunity to discover genetic changes across the entire genomes or protein-coding sequences in human cancers at a single-nucleotide level, which could be enabled the discovery of recurrent mutations in IDH1/2, and DNMT3A in adult AML. However, these mutations are extremely rare in pediatric AML. Methods To reveal a complete registry of gene mutations and other genetic lesions, whole-exome resequencing of paired tumor-normal DNA from 19 cases were analyzed with a mean coverage of approximately x100, and 82 % of the target sequences were analyzed at more than x20 depth on average. We selected various cases in age, FAB classification and karyotypes, including 5 cases with core-binding-factor AML, 6 cases with MLL-rearrangement and 2 acute megakaryoblastic leukemia cases. Results and Discussion A total of 80 somatic mutations or 4.2 mutations per sample were identified. As the mean number of somatic mutations reported in adult AML was about ten, somatic mutations in pediatric AML might be fewer than in adult AML. Many of the recurrent mutations identified in this study involved previously reported targets in AML, such as FLT3, CEBPA, KIT, CBL, NRAS, WT1 and EZH2. On the other hand, several genes were newly identified in the current study, including BRAF, BCORL1, DAZAP1, CUL2, ASXL2, MLL2, MLL3, SMC3 and RAD21. Among these, what immediately drew our attention were SMC3 and RAD21, because they belong to the major cohesin components. Cohesin is a multimeric protein complex conserved across species and composed of four core subunits, i.e., SMC1, SMC3, RAD21, and STAG proteins, forming a ring-like structure. Cohesin is engaged in cohesion of sister chromatids during cell division, post-replicative DNA repair, and regulation of global gene expression through long-range cis-interactions. Furthermore, we also drew our attention to BCORL1, because it is a transcriptional corepressor, and can bind to class II histone deacetyllases (HDAC4, HDAC5, HDAC7), to interact with the CTBP1 corepressor, and to affect the repression of E-cadherin. BCOR is also a transcriptional corepressor and play a key role in the regulation of early embryonic development, mesenchymal stem cell function and hematopoiesis. To confirm and extend the initial findings in the whole-exome sequencing, we studied mutations of the above 8 genes, in pediatric AML (N = 190) using a high-throughput mutation screen of pooled DNA followed by confirmation/ identification of candidate mutations. In total, 32 mutations were identified in 31 of the 190 specimens of pediatric AML [BCOR (N = 7), BCORL1 (N = 7), RAD21 (N = 7), SMC3 (N = 5), SMC1A (N = 1), and STAG2 (N = 3)]. The mutually exclusive pattern of the mutations in these BCOR, BCORL1 and cohesin components genes was confirmed in this large case series, suggesting a common impact of these mutations on the pathogenesis of pediatric AML. The 4-year overall survival of these cases with major cohesin components gene mutations was relatively favorable (12/16 or 75.0%), but the outcome of cases with BCOR or BCORL1 cases was unfavorable (8/14 or 57.1%). Conclusion Whole exome resequencing unmasked a complexity of gene mutations in pediatric AML genomes. Our results indicated that a subset of pediatric AML represents a discrete entity that could be discriminated from the adult counterpart, in terms of the spectrum of gene mutations. Disclosures: No relevant conflicts of interest to declare.