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Добірка наукової літератури з теми "U2AF2"

Автор: Grafiati

Опубліковано: 10 травня 2025

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Статті в журналах з теми "U2AF2"

Warnasooriya, Chandani, Callen F. Feeney, Kholiswa M. Laird, Dmitri N. Ermolenko, and Clara L. Kielkopf. "A splice site-sensing conformational switch in U2AF2 is modulated by U2AF1 and its recurrent myelodysplasia-associated mutation." Nucleic Acids Research 48, no. 10 (April 28, 2020): 5695–709. http://dx.doi.org/10.1093/nar/gkaa293.

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Abstract An essential heterodimer of the U2AF1 and U2AF2 pre-mRNA splicing factors nucleates spliceosome assembly at polypyrimidine (Py) signals preceding the major class of 3′ splice sites. U2AF1 frequently acquires an S34F-encoding mutation among patients with myelodysplastic syndromes (MDS). The influence of the U2AF1 subunit and its S34F mutation on the U2AF2 conformations remains unknown. Here, we employ single molecule Förster resonance energy transfer (FRET) to determine the influence of wild-type or S34F-substituted U2AF1 on the conformational dynamics of U2AF2 and its splice site RNA complexes. In the absence of RNA, the U2AF1 subunit stabilizes a high FRET value, which by structure-guided mutagenesis corresponds to a closed conformation of the tandem U2AF2 RNA recognition motifs (RRMs). When the U2AF heterodimer is bound to a strong, uridine-rich splice site, U2AF2 switches to a lower FRET value characteristic of an open, side-by-side arrangement of the RRMs. Remarkably, the U2AF heterodimer binds weak, uridine-poor Py tracts as a mixture of closed and open U2AF2 conformations, which are modulated by the S34F mutation. Shifts between open and closed U2AF2 may underlie U2AF1-dependent splicing of degenerate Py tracts and contribute to a subset of S34F-dysregulated splicing events in MDS patients.

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Biancon, Giulia, Poorval Joshi, Torben Hunck, Yimeng Gao, Valentina Botti, Ashley Qin, Mukhtar Sadykov, et al. "U2AF1 Driver Mutations in Hematopoietic Disorders Alter but Do Not Abrogate RNA Binding and Enlighten Structural Dependencies of the U2AF-RNA Complex." Blood 134, Supplement_1 (November 13, 2019): 1230. http://dx.doi.org/10.1182/blood-2019-130759.

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Among genetic aberrations responsible for ineffective hematopoiesis in myelodysplastic syndromes (MDS) and acute myeloid leukemia, somatic mutations in splicing factors such as U2AF1 are of significant interest as they are recurrent, mutually exclusive and early occurring. U2AF1 participates in mRNA splicing through the recognition of the intronic 3' splice site, forming the U2AF complex as a heterodimer with U2AF2. Heterozygous hotspot mutations at S34 or Q157, in the two U2AF1 zinc fingers respectively, result in sequence dependent aberrant splicing, suggestive of altered RNA binding. The mechanism by which these mutations alter U2AF1-U2AF2-RNA interactions has to date not been elucidated, yet understanding the structure-function relationship is critical to devise novel therapeutic strategies that either aim to correct or exploit RNA binding and splicing defects. To address this issue, we profiled the transcriptome of HEL erythroleukemic cell lines expressing wild-type (WT) and mutant U2AF1. U2AF1 S34F and Q157R mutants induced widespread alterations in splicing patterns of 3250 and 1791 genes respectively, with an overlap of 23.8% genes. On the other hand, we observed only minor alterations in gene expression levels. Meta-analysis and comparison with published RNA sequencing datasets on U2AF1 mutants revealed both conserved and unique splicing changes, with a strong enrichment for genes involved in cell cycle (P=6.7E-15) and DNA repair (P=2.6E-5). Confirming previous literature, U2AF1 S34F preferentially leads to the exclusion of exons preceded by 3' splice sites bearing an intronic UAG motif, while U2AF1 Q157R preferentially excludes exons starting with the AGA motif (Figure 1A). Collectively, the S34F mutation has a stronger effect on splicing, ultimately decreasing the global translation state of cells. To understand how mutations eventually result in the observed splicing alterations, we also profiled with unprecedented resolution the RNA interactome of the physiological and pathological U2AF heterodimer. We first performed enhanced crosslinking immunoprecipitation (eCLIP) on U2AF1 WT, U2AF1 mutants and U2AF2. Comparison of U2AF1 and U2AF2 binding profiles revealed a high degree of similarity, suggesting that they mostly bind to RNA as a tight dimer. Only by performing fractionated eCLIP on U2AF1 we were able to isolate, at the molecular level, the individual contributions of the U2AF components in the recognition of the 3' splice site. In particular, we deconvolved the U2AF2 signal, insisting on the polypyrimidine region, and the U2AF1 signal, peaking on the AG dinucleotide at the intronic end (Figure 1B). Importantly, the S34F mutant displays an aberrant binding profile, with a specific peak on the nucleotide in position -3, matching the sequence specificity previously observed in aberrant splicing events (Figure 1A-B). Systematic analysis of bound junctions suggests a complex model where the S34F mutation does not simply abrogate the ability of U2AF1 to bind splicing junctions ending with the UAG sequence, but rather alters the conformation of the U2AF complex bound to RNA, resulting in a differential ability to effectively recruit the U2 complex. To confirm this model, we identified and validated a set of gain-of-function splice junctions in genes contributing to hemopoiesis and cell cycle, characterized by increased binding of U2AF1 S34F mutant and parallel decreased binding of U2AF2. In summary, we identified novel RNA sequence and structure determinants of U2AF complex conformation, uncovered by the binding alterations induced by the U2AF1 S34F mutation. Our data further dissect the complexities of post-transcriptional regulation and provide the basis for development of U2AF directed cancer therapies. Disclosures Hunck: B**hringer-Ingelheim Foundation.: Other: During my stay in the Halene Lab I was founded by an MD fellowship.

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Yang, Chao-Yie, Xinrui Yuan, Mona Kazemi Sabzvar, Arda Durmaz, Krishnapriya Chinnaswamy, Jeanne Stuckey, Seth J. Corey, Jaroslaw P. Maciejewski, and Valeria Visconte. "Small-Molecule U2 Auxiliary Factor Homology Motif (UHM) Domain Inhibitors Cause Splicing Pattern Changes in U2AF1 Mutant Leukemia Cells and Induce Sub-G1 Cell Cycle Arrest." Blood 142, Supplement 1 (November 28, 2023): 115. http://dx.doi.org/10.1182/blood-2023-190365.

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Mutations in factors involved in the spliceosomal pathway have emerged to be an important contributor to the development of myeloid neoplasms including MDS and secondary AML (sAML). A set of frequently mutated genes encoding RNA splicing factors including SF3B1, U2AF1, SRSF2, and ZRSR2 or haploinsufficiency of LUC7L2 have beenreported, but pharmacological intervention targeting these genes remains limited and under-developed. Combination of mutations of these splicing factors are rarely found in patients indicating that multiple defects in a spliceosome pathway may be deleterious. Heterozygous mutation in U2AF1 found in MDS leads to the acquisition of the neomorphic mutant U2AF1 (U2AF1 wt) that relies on wild-type U2AF1 (U2AF1 wt) to survive and proliferate. To support our hypothesis, we undertook a discovery campaign to identify small-molecule compounds targeting U2AF1. By recognizing the challenge of discovering compounds selectively targeting the mutant zinc-finger domains in U2AF1 found clinically, we devised a tractable intervention strategy to inhibit the UHM domain of U2AF1 (U2AF1-UHM). U2AF1-UHM binds with U2AF2 to form a protein complex (U2AF1/U2AF2) that recognizes the 3' splice site in mRNA processing. U2AF1-UHM inhibitors may decrease the binding between U2AF1 and U2AF2 and abrogate U2AF1/U2AF2 functions to change expression patterns of protein isoforms. To identify hit compounds for development, we performed screening of ~3000 fragment molecules against U2AF1-UHM using the thermal shift assay. Two of the top hits were derivatives of the same chemical scaffold. We verified that both hits inhibited the binding of U2AF1-UHM and U2AF2-ULM (U2AF ligand motifs) in our Homogenous Time-Resolved Fluorescence (HTRF) assay. We next evaluated the top hit, SF-1-8, in our K562-U2AF1 S34F mutant cell line and obtained an IC50 at the micromolar range. In contrast, SF-1-8 had no activity in K562-U2AF1 wt cell line and bone marrow cells obtained from healthy individuals. Based on SF-1-8, we performed chemical modifications to develop structure-activity relationship (SAR) of SF-1-8 and obtained SF-1-50 that was two-fold more potent than SF-1-8. To assess the selectivity of SF-1-8 and analogs to other UHM containing proteins, we further determined the IC50 values of our SF-1-8 analogs to RBM39-UHM, SPF45-UHM, and PUF60-UHM to construct the selectivity profiles of our compounds. The selectivity profiles of SF-1-8 and SF-1-50 showed they were selectively more effective to U2AF1-UHM than RBM39-UHM, SPF45-UHM, and PUF60-UHM. We then studied pathways impacted by these inhibitors in K562-U2AF1 S34F cells by performing RNA-seq in K562-U2AF1 S34F cells treated with SF-1-8 at 5 uM and control. We found that 36 and 63 genes were significantly (p <0.002) up- and down-regulated respectively by SF-1-8 in K562-U2AF1 S34F cells. Downregulated genes included CBL, CBLL1, and a subset of collagen genes ( COL1, COL3, COL5) and upregulated genes included ATF3 and BCL2. When analyzing the transcript changes affected by SF-1-8, we identified substantial protein isoform changes in genes involved with proteosome, endocytosis, apoptosis, extracellular matrix/cell adhesion, histones, and stress response. Primary effects from changes of protein isoform patterns ameliorated the restoration of the trans-Golgi network ( ERGIC3, COPB2), secretory pathway ( RUSC1, AP4E1) and impairment of clathrin mediated endocytosis and endosome-lysosome transport ( CBL, PICALM, VAMP7, ASAP1). NKM-1 cell line was previously characterized to carry U2AF1 mutation. We also found SF-1-50 caused accumulation of sub-G1 cells in NKM-1 cells in a dose-dependent manner. In summary, SF-1-8 caused disruption of extra- and intracellular protein transport in K562-U2AF1 S34F cells and represented a new class of small-molecule inhibitors to target U2AF1-UHM. Further optimization of this class of compounds will allow us to develop effective chemical probes for study in the U2af1 murine models and assess the potential of U2AF1 as a therapeutic target in MDS and sAML.

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Biancon, Giulia, Poorval Joshi, Torben Hunck, Josh Zimmer, Yimeng Gao, Martin Machyna, Valentina Botti, et al. "High-Resolution Binding Atlas of U2AF1 Mutants Uncovers New Complexity in Splicing Alterations and Kinetics in Myeloid Malignancies." Blood 136, Supplement 1 (November 5, 2020): 3–4. http://dx.doi.org/10.1182/blood-2020-142854.

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Spliceosomal gene mutations function as drivers of hematologic malignancies and other cancers with an occurrence of more than 50% in myelodysplastic syndromes and secondary acute myeloid leukemia. Hotspot mutations S34F and Q157R in the two zinc finger domains of the splicing factor U2AF1, forming with U2AF2 the U2AF complex that recognizes 3' splice site (3'SS) of U2 introns, alter exon usage in a sequence-specific manner. However, how pathological U2AF1 mutations disrupt ordered splicing, from binding to recruitment of cooperating RNA binding proteins and ultimately splicing kinetics, is still not known at the molecular level. To obtain unique insights into in vivo RNA binding mechanisms, we performed fractionated enhanced crosslinking immunoprecipitation coupled with deep RNA sequencing (freCLIP-seq) on human erythroleukemia (HEL) cells expressing wild-type (WT) or mutant (S34F, Q157R) U2AF1. Transcriptome-wide analysis of binding at single nucleotide resolution in light and heavy fractions, corresponding respectively to U2AF1 only and U2AF complex, allowed to: i) deconvolute U2AF1 signal peaking over the AG dinucleotide at the intronic end of the 3'SS region, and U2AF2 signal sitting on the adjacent polypyrimidine tract (PPT); ii) identify conformational changes in mutant U2AF1 binding with a novel peak in position -3 of the 3'SS region for S34F and in position +1 for Q157R. Alternative splicing analysis on newly collected RNA-seq data showed that less included exons present higher probability of U in position -3 for S34F and A in position +1 for Q157R, pinpointing a match with nucleotide positions affected by aberrant binding in freCLIP-seq. In both U2AF1 mutants, aberrant binding and splicing mechanisms affected genes involved in mRNA processing and transport (P-value<0.01) highlighting the involvement of U2AF1 mutations in the dysregulation of these key biological processes. We then performed a combined analysis of differential binding and aberrant splicing in U2AF1 mutants vs WT considering 4 categories: ">inclusion/>binding", "<inclusion/<binding", "<inclusion/>binding", ">inclusion/<binding". The first 2 categories correspond to the loss-of-function binding model suggested in literature to explain the splicing outcome of U2AF1 mutations: U2AF1 mutants bind certain splicing junctions with less affinity, leading to their exclusion. The last 2 categories represent a non-canonical gain-of-function model where increased mutant U2AF1 binding results in the impairment of the splicing machinery. Surprisingly, while Q157R mainly exhibited a loss-of-function mechanism where ineffective splicing is related to absence of binding ("<inclusion/<binding", 51.1%), S34F mostly follows a gain-of-function mechanism affecting splicing progression by an increased, yet skewed, binding. The most represented category was, indeed, "<inclusion/>binding" with 123 events out of 309 (Figure 1A). Moreover, differential binding was not dependent on specific nucleotides in position -3: events characterized by increased S34F binding (Figure 1B, top), as well as events characterized by decreased S34F binding (Figure 1B, bottom), showed -3U in less included exons or -3C in more included exons. The binding analysis across the 4 categories showed that increased S34F binding was associated with reduced U2AF2 binding (Figure 1C, top) particularly in less included exons, while decreased S34F binding was associated with increased U2AF2 binding (Figure 1C, bottom) especially in more included exons. Finally, analysis of branch point and splice junction features revealed that PPT strength influences the splicing outcome with "<inclusion/>binding" category characterized by a weak PPT that impairs U2AF2 binding in the presence of skewed U2AF1 S34F binding (Figure 1D). Additionally, transcriptome-wide RNA kinetics analysis by TimeLapse-seq demonstrated that U2AF1 S34F and Q157R, compared to WT, globally decrease synthesis of aberrantly spliced and bound 3'SS regions. Of note, this shutdown effect was particularly evident in the downstream exons pointing towards a role of U2AF1 mutations in a widespread alteration of RNA synthesis and splicing dynamics. Collectively, these results disclose novel molecular mechanisms of pathogenic U2AF1 mutations in the context of myeloid malignancies and provide the basis for the development of effective U2AF1 directed therapeutic strategies. Disclosures Hunck: Boehringer Ingelheim Fonds: Other: MD Fellowship.

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Yuan, Xinrui, Mona Kazemi Sabzvar, Amol D. Patil, Arda Durmaz, Jaroslaw Maciejewski, Valeria Visconte, and Chao-Yie Yang. "Targeting Poly(U) Binding Splicing Factor 60 (PUF60): A Small-Molecule Inhibitor Shows Anti-Leukemic Activity and Impacts Cell Cycle in Leukemia Models." Blood 144, Supplement 1 (November 5, 2024): 7470. https://doi.org/10.1182/blood-2024-210241.

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The emerging role of altered RNA splicing in the development of myeloid neoplasms including MDS and AML has received wide attention. Facilitating genes, including the frequently mutated splicing factors, SF3B1, U2AF1, and SRSF2, have been reported to play a key role in leukemogenesis. Pharmacological intervention targeting cells harboring these mutations has been pursued, but limited agents have been reported. Rare events of more than one hit in splicing factors were found in MDS and AML patients' samples. This suggests that inhibiting another target in the splicing process may overcome the threshold of survival in these vulnerable cells carrying splicing factor mutations and induce toxicity. The concept has been demonstrated in the case of leukemia cells carrying U2AF1 mutations being vulnerable to inhibitors modulating wild-type SF3B1 function. The primary function of U2AF1 is to form a complex with U2AF2 for 3‘ splice site (SS) definition in RNA splicing and lower frequency U2AF2 mutations are also detected in MDS patients, underlying the significance of dysfunctional 3‘ SS definition as a potential facilitator of leukemogenesis. Here, we hypothesize that compounds inhibiting proteins participating in 3' SS selection may disrupt isoform patterns in leukemia cells. These agents may act alone or serve as a second hit in the RNA processing to invoke additional vulnerabilities to leukemia cells carrying the most frequent splicing factor mutations. Definition of 3' SS by U2AF2/U2AF1 is mediated by the recognition of the polypyridine tract (PPT) by U2AF2 and the binding of U2AF1 to the conserved AG dinucleotides at the 3' SS. Like U2AF2, PUF60 contains two zinc-finger domains, recognizing the polyuridine tract preceding 3' SS, and a U2 homology motif (UHM) domain that engages in protein-protein interaction with partner proteins including U2AF2, SF1, and SF3B1. Different from the U2AF1/U2AF2 complex, PUF60 does not have a protein domain to bind to the exon intron boundary junction at the 3' SS. PUF60 has been reported to enhance the splicing activity of U2AF1/U2AF2, but also directly regulates alternative splicing of a subset of genes. A recent finding indicated that knockout of PUF60 leads to alternative splicing switching of CDC25 from isoform A to isoform C to induce cell cycle arrest at G2/M in solid tumors. Leukemia patients carrying PUF60 overexpression have also been found to have less progression free survival (https://ualcan.path.uab.edu/cgi-bin/TCGA-survival1.pl?genenam=PUF60&ctype=LAML) compared to patients with low expression of PUF60. To support our hypothesis, we undertook an inhibitor development campaign to discover small-molecule compounds selectively targeting PUF60. Based on a relatively less selective and weak inhibitor to the UHM domain, SF-153, we conducted chemical modifications and obtained a PUF60 inhibitor, SF2-69, with >15-fold selectivity against U2AF1, RBM39, SPF45, and U2AF2. We found SF2-69 had an IC50 value of ~3 mM in NKM-1 and K562 leukemia cell lines. In the cell cycle analysis, we found SF2-69 increased S and subG1 cell population in NKM-1 at 24h, but induced G1 arrest in K562 at 48h in a dose dependent manner. In comparison, E7820, an RBM39 degrader, increased G2/M phase in both NKM-1 and K562. RNA-seq analysis of NKM-1 treated with SF2-69 after 24h revealed that SF2-69 upregulated a set of genes participating in cholesterol biosynthesis, NME1-NME2 (a tumor suppressor kinase) and downregulated PLK1, a kinase that phosphorylates and activates CDC25C in G2/M transition. Because K562 is p53-null and NKM-1 has wild-type p53, SF2-69 likely induced p53-dependent and p53-independent responses in NKM-1 and K562 cells, respectively. In summary, SF2-69 is a new selective PUF60 inhibitor which disrupts cell cycle progression in leukemia cell lines by modulating p53-mediated responses. Upregulation of cholesterol biosynthesis may be a feedback loop to counteract the inhibition of PUF60 by SF2-69. Further optimization of SF2-69 will allow us to develop more effective and selective chemical probes for studying the role of PUF60 overexpression in leukemia and the potential use of PUF60 inhibitors in MDS and AML cells carrying splicing factor mutations.

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Akef, Abdalla, Kathy McGraw, Steven D. Cappell, and Daniel R. Larson. "Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation." PLOS Biology 18, no. 11 (November 2, 2020): e3000920. http://dx.doi.org/10.1371/journal.pbio.3000920.

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U2 Small Nuclear RNA Auxiliary Factor 1 (U2AF1) forms a heterodimeric complex with U2AF2 that is primarily responsible for 3ʹ splice site selection. U2AF1 mutations have been identified in most cancers but are prevalent in Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML), and the most common mutation is a missense substitution of serine-34 to phenylalanine (S34F). The U2AF heterodimer also has a noncanonical function as a translational regulator. Here, we report that the U2AF1-S34F mutation results in specific misregulation of the translation initiation and ribosome biogenesis machinery. The net result is an increase in mRNA translation at the single-cell level. Among the translationally up-regulated targets of U2AF1-S34F is Nucleophosmin 1 (NPM1), which is a major driver of myeloid malignancy. Depletion of NPM1 impairs the viability of the U2AF1-S34F mutant cells and causes ribosomal RNA (rRNA) processing defects, thus indicating an unanticipated synthetic interaction between U2AF1, NPM1, and ribosome biogenesis. Our results establish a unique molecular phenotype for the U2AF1 mutation that recapitulates translational misregulation in myeloid disease.

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Maji, Debanjana, Eliezra Glasser, Steven Henderson, Justin Galardi, Mary J. Pulvino, Jermaine L. Jenkins, and Clara L. Kielkopf. "Representative cancer-associated U2AF2 mutations alter RNA interactions and splicing." Journal of Biological Chemistry 295, no. 50 (October 5, 2020): 17148–57. http://dx.doi.org/10.1074/jbc.ra120.015339.

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High-throughput sequencing of hematologic malignancies and other cancers has revealed recurrent mis-sense mutations of genes encoding pre-mRNA splicing factors. The essential splicing factor U2AF2 recognizes a polypyrimidine-tract splice-site signal and initiates spliceosome assembly. Here, we investigate representative, acquired U2AF2 mutations, namely N196K or G301D amino acid substitutions associated with leukemia or solid tumors, respectively. We determined crystal structures of the wild-type (WT) compared with N196K- or G301D-substituted U2AF2 proteins, each bound to a prototypical AdML polypyrimidine tract, at 1.5, 1.4, or 1.7 Å resolutions. The N196K residue appears to stabilize the open conformation of U2AF2 with an inter-RNA recognition motif hydrogen bond, in agreement with an increased apparent RNA-binding affinity of the N196K-substituted protein. The G301D residue remains in a similar position as the WT residue, where unfavorable proximity to the RNA phosphodiester could explain the decreased RNA-binding affinity of the G301D-substituted protein. We found that expression of the G301D-substituted U2AF2 protein reduces splicing of a minigene transcript carrying prototypical splice sites. We further show that expression of either N196K- or G301D-substituted U2AF2 can subtly alter splicing of representative endogenous transcripts, despite the presence of endogenous, WT U2AF2 such as would be present in cancer cells. Altogether, our results demonstrate that acquired U2AF2 mutations such as N196K and G301D are capable of dysregulating gene expression for neoplastic transformation.

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Grammatikakis, Ioannis, Amit Behera, Corrine Corrina R Hartford, Erica C. Pehrsson, XiaoLing Li, Yongmei Zhao, Biraj Shrethsa, et al. "Abstract A013: Molecular mechanisms of intron retention in Long Non-Coding RNAs." Molecular Cancer Therapeutics 23, no. 11_Supplement (November 14, 2024): A013. http://dx.doi.org/10.1158/1538-8514.rnadrivers24-a013.

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Abstract Intron retention (IR) is a form of alternative splicing in which an intron that should be spliced out from a precursor transcript, is retained in the mature RNA after the splicing is completed. Although there is emerging evidence of widespread IR in protein-coding genes and long noncoding RNAs (lncRNAs), the underlying molecular mechanisms remain largely unclear. Here, we report the discovery of novel transcripts from the p53-induced lncRNA PURPL, in which intron 2 is retained. To determine the molecular mechanism(s) of IR in PURPL, we conducted a CRISPR-based screen in 3 different cell lines. For this purpose, we utilized a genome-wide guide RNA library expressing a reporter minigene containing the sequence of PURPL intron 2 and its flanking exons. Considering the Percent Intron Retention as readout, we unexpectedly identified proteins of the basal splicing machinery as potential promoting factors of PURPL IR, including the U2-Auxiliary Factor 2 (U2AF2) splicing factor which was one of the top hits of the screen. We next analyzed ENCODE eCLIP-seq datasets to identify RNA binding proteins that could regulate intron 2 and decided to focus on U2AF2 which showed the highest number of binding sites and strongest eCLIP signals within PURPL intron 2 sequence. We validated the effect of U2AF2 by knocking it down, confirming that U2AF2 is a positive regulator of PURPL intron 2 retention as opposed to its canonical function. We also identified the RNA Binding Protein SON as a splicing regulator that acts as an antagonist of U2AF2 in regulating PURPL intron 2 retention. To determine the global impact of U2AF2 knockdown, we performed Iso-Seq and RNA-seq upon U2AF2 depletion. We found that although U2AF2 predominantly acts to promote the splicing of introns in most cellular transcripts, it promotes intron retention in a subset of transcripts. One of these targets is MALAT1, a lncRNA known to play role in splicing by interacting with splicing factors in nuclear speckles. Interestingly, U2AF2 depletion results in MALAT1 exclusion from nuclear speckles. We are currently in the process of characterizing the effect of U2AF2 in the function of the two lncRNAs. These data provide mechanistic insights on PURPL and MALAT1 splicing and function and reveal a previously unrecognized non-canonical function of U2AF2 in promoting intron retention. Citation Format: Ioannis Grammatikakis, Amit Behera, Corrine Corrina R Hartford, Erica C Pehrsson, XiaoLing Li, Yongmei Zhao, Biraj Shrethsa, Tayvia Brownmiller, Natasha J Caplen, Kannanganattu V Prasanth, Thomas Gonatopoulos-Pournatzis, Ashish Lal. Molecular mechanisms of intron retention in Long Non-Coding RNAs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A013.

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Kang, Hyun-Seo, Carolina Sánchez-Rico, Stefanie Ebersberger, F. X. Reymond Sutandy, Anke Busch, Thomas Welte, Ralf Stehle, et al. "An autoinhibitory intramolecular interaction proof-reads RNA recognition by the essential splicing factor U2AF2." Proceedings of the National Academy of Sciences 117, no. 13 (March 18, 2020): 7140–49. http://dx.doi.org/10.1073/pnas.1913483117.

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The recognition of cis-regulatory RNA motifs in human transcripts by RNA binding proteins (RBPs) is essential for gene regulation. The molecular features that determine RBP specificity are often poorly understood. Here, we combined NMR structural biology with high-throughput iCLIP approaches to identify a regulatory mechanism for U2AF2 RNA recognition. We found that the intrinsically disordered linker region connecting the two RNA recognition motif (RRM) domains of U2AF2 mediates autoinhibitory intramolecular interactions to reduce nonproductive binding to weak Py-tract RNAs. This proofreading favors binding of U2AF2 at stronger Py-tracts, as required to define 3′ splice sites at early stages of spliceosome assembly. Mutations that impair the linker autoinhibition enhance the affinity for weak Py-tracts result in promiscuous binding of U2AF2 along mRNAs and impact on splicing fidelity. Our findings highlight an important role of intrinsically disordered linkers to modulate RNA interactions of multidomain RBPs.

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Biancon, Giulia, Poorval Joshi, Joshua T. Zimmer, Torben Hunck, Yimeng Gao, Mark D. Lessard, Edward Courchaine, et al. "U2AF1 Mutations Enhance Stress Granule Response in Myeloid Malignancies." Blood 138, Supplement 1 (November 5, 2021): 321. http://dx.doi.org/10.1182/blood-2021-149618.

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Abstract Somatic mutations in splicing factor genes are drivers of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The splicing factors U2AF1 and U2AF2 form the U2AF heterodimer that is critical in the 3' splice site (3'SS) recognition and in the recruitment of U2 small nuclear ribonucleoproteins for the activation of the spliceosome complex. U2AF1 carries hotspot mutations in its two RNA binding motifs; yet the molecular mechanisms affecting the splicing process and promoting clonal advantage remain unclear, albeit necessary to develop effective targeted therapies. We applied a multi-omics approach comparing the activities of two U2AF1 mutants (S34F and Q157R) in MDS/AML cell lines and primary samples. Using a novel approach of fractionated enhanced crosslinking immunoprecipitation coupled with deep RNA-sequencing (freCLIP-seq), we mapped transcriptome-wide binding at nucleotide resolution and we identified conformational changes in mutant vs wild-type U2AF1 binding. Specifically, we observed an emergent peak in position -3 of the 3'SS for the S34F mutant and in position +1 for the Q157R mutant, matching the critical positions observed by differential splicing analysis on RNA-seq data. Altered U2AF1-RNA binding compromised U2AF2-RNA interactions, resulting predominantly in exon exclusion and intron retention. Combined binding-splicing analysis showed that while the Q157R mutant mainly exhibits loss of binding, the S34F mutant follows a gain-of-binding pattern, where splicing progression appears impaired by increased mutant binding. Functional analysis of genes affected by both binding and splicing alterations revealed that U2AF1 mutants alter RNA granule biology, affecting in particular stress granule-enriched transcripts and proteins. Stress granules are membrane-less cytoplasmic assemblies of RNAs and RNA binding proteins that improve cellular adaptation in response to stress conditions. Increased stress granule formation has been linked to tumorigenesis as a strategy exploited by cancer cells to regulate gene expression and signal transduction, enhancing their fitness under stress. To probe how aberrant binding and splicing of stress granule components affected stress granule biology, we assessed stress granule formation in U2AF1 mutant vs wild-type cells at steady state and after stress induction with sodium arsenite treatment. Immunofluorescent staining followed by confocal imaging demonstrated that U2AF1 mutations enhance stress granule formation upon arsenite stress in both cell lines and primary samples. RNA turnover analysis by TimeLapse-seq confirmed that U2AF1 S34F and Q157R mutations promote stability/synthesis of transcripts that are enriched in stress granules and determine degradation/shutdown of transcripts that are depleted in stress granules, providing a molecular explanation for the increase in stress granules observed by imaging. Finally, we were able to corroborate our observations by single-cell RNA-seq in patient-derived U2AF1-mutant MDS blasts, establishing the causal link between U2AF1 mutations and upregulation of stress granule components. Collectively, this multi-omics analysis identified biological processes directly influenced by mutant U2AF1 binding and splicing, laying the foundation for a new paradigm where splicing factor mutations enhance stress granule formation by acting on the availability of their RNA and protein components. The enhanced formation of stress granules potentially fosters the stress adaptation of U2AF1-mutant cells, contributing to their clonal advantage in MDS/AML. Stress granule perturbations may therefore represent a novel therapeutic vulnerability in U2AF1-mutant MDS/AML patients and possibly in patients carrying other splicing factor mutations. Disclosures Hunck: Boehringer Ingelheim: Other: Fellowship.

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Дисертації з теми "U2AF2"

Le, Scanf Enora. "Caractérisation des altérations de l’épissage des ARN pré-messagers dans les cancers digestifs à microsatellites instables." Electronic Thesis or Diss., Brest, 2024. http://www.theses.fr/2024BRES0113.

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L’exon en aval dans l’ARNm, dépendant du gène considéré et de la taille de la délétion dans le SP-MS. Nous montrons qu’un SP-MS raccourci présente moins d’affinité pour la protéine U2AF2 in vitro et que la mutation U2AF1-S34F ou le knock-down d’U2AF1 peuvent mimer l’effet de l’altération du PyT. Enfin, les transcrits matures dépourvus de l'exon cible peuvent être soit stables, soit dégradés par le système NMD de surveillance des codons non-sens prématurés, et ne sont donc pas dotés d'une capacité spécifique à éviter la dégradation. Nous supposons que les protéines aberrantes, qui peuvent être traduites à partir de ces ARNm alternatifs, pourraient participer à l’oncogenèse par la production de néo-antigènes associés aux tumeurs
Gastric and colorectal cancers are among the most common and deadly cancers. The MSI (Microsatellite Instability) subtype, which accounts for 15-20% of these cancers is deficient in the DNA mismatch repair system, thus leading to microsatellite instability. The polypyrimidine tract (SP-MS) that seats at the 3’ end of the intron, can be considered as a microsatellite-like structure that participates to the splicing of the downstream exon by interacting mainly with the U2AF2 protein and forms a heterodimer with the U2AF1 protein, which recognizes the AG dinucleotide 3’ acceptor splice site. Shortening of the PyT, in MSI cancers, can lead to splicing changes. We have identified a massive alteration of pre-messenger RNA splicing in digestive MSI cancers, in association with SP-MS shortening. These splicing defects are characterized by downstream exon skipping in mRNA, depending both on the gene considered and the size of the deletion in the SP-MS. We showed that a shortened SP-MS has less affinity for the U2AF2 protein in vitro and the mutation or knock-down of U2AF1 can mimic the effect of SP-MS alterations. Finally, mature transcripts devoid of the target exon can be either stable or degraded by the nonsense-mediated mRNA decay surveillance mechanism, and thus, are not endowed with a specific ability to avoid degradation. We surmise that the aberrant proteins that may be translated from these alternative mRNAs could participate in oncogenic mechanisms through the production of tumour-associated neo-antigens

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Laaref, Abdelhamid Mahdi. "Contribution of U2AF1, NCBP1 and eIF4A3 to the control of pluripotency maintenance and cell fate determination." Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT146.

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Contribution de U2AF1, NCBP1 et eIF4A3 dans le contrôle du maintien de la pluripotence et le devenir cellulaire.Les mécanismes de maturation du transcrit primaire peuvent profondément affecter la diversité et la fonction des protéines produites à partir d’un gène unique dans le but de mettre en place un programme complexe impliqué dans le maintien de pluripotence et/ou l’initiation de la différenciation des cellules souches humaines. Les réseaux transcriptionnels régulant la pluripotence et la différenciation ont été intensément étudiés contrairement au rôle de l’épissage alternatif dans ces mécanismes, rôle qui pour le moment reste mal compris et pour lequel il n’existe que très peux d’exemples de groupes de gènes subissant un changement général de variant d’épissage aboutissant à la modification du devenir cellulaire. Notre objectif est d’identifier les composés essentiels du spliceosome qui sont impliqués dans le maintien de la pluripotence et la différenciation précoce dans les trois feuillets embryonnaires et d’explorer leurs rôles dans ces processus. Via l’analyse de données de séquençage d’ARN nous avons identifié plusieurs facteurs d’épissage différentiellement exprimés entre les cellules souches et les trois feuillets embryonnaires. Parmi ces facteurs nous focaliserons notre étude sur les facteurs préférentiellement surexprimés dans les cellules souches, qui par conséquent devraient y jouer un rôle primordial. Les candidats sélectionnés, U2AF1, NCBP1 et eIF4A3 ont été déplétés dans des cellules souches en utilisant un système shRNA inductible puis une analyse de séquençage ARN à haut débit a été effectuée pour comprendre les changements du transcriptome induits par ces déplétions. La déplétion d’U2AF1 entraine un changement majeur de l’expression de gènes impliqués dans le développement alors que la déplétion de NCBP1 et eIF4A3 entraine un changement d’expression de gènes impliqués dans le métabolisme, le remodelage de la chromatine et le développement. Des analyses complémentaires ont permis de mettre en lumière une régulation transcriptionnelle et post-transcriptionnelle des gènes différentiellement exprimés dans les conditions étudiées. L’épissage alternatif a pour ça part été modifié par les trois déplétions de manière individuelle. Un programme d’épissage tissu spécifique a été associé à chaque candidat et les conséquences de chaque programme seront décrites au niveau du contrôle qualité de l’ARNm et de la synthèse protéique.Nos résultats construisent une nouvelle vision concernant le rôle des composés essentiels du spliceosome dans le contrôle du devenir cellulaire à travers la modulation de l’épissage alternatif. Cet apport ajoute une nouvelle variable au contrôle de l’expression des gènes et permettra de mieux comprendre les mécanismes du développement précoce et de la diversité tissulaire
Contribution of U2AF1, NCBP1 and eIF4A3 to the control of pluripotency maintenance and cell fate determination.Alternative pathways for processing the primary transcript can profoundly affect the diversity and function of the protein products that are generated from a single gene to set up complex programs involved in pluripotency and/or differentiation of human Embryonic Stem Cells (hESCs). While transcriptional networks regulating pluripotency and differentiation has been intensively studied, the role of Alternative Splicing (AS) in this process is not yet completely understood and clear examples of concerted switching of multiple genes from one isoform to another have not been demonstrated. Our goal is to identify Core Spliceosomal Factors (CSF), involved in the control of pluripotency maintenance, early differentiation into the three germ layers, and to explore their role in these processes. By RNA-Seq data analysis, we have identified several splicing factors that are differentially expressed between pluripotent stem cells and the three of the germ layers. Among these identified candidates, we focused on the factors that are more highly expressed in pluripotent stem cells, thereby they play a specific role in pluripotency maintenance. The selected candidates, U2AF1, NCBP1 and eIF4A3 were depleted in pluripotent stem cells using inducible shRNA system and RNA-Seq analyzes have been performed to understand transcriptomic changes induced by these depletions. U2AF1 depletion causes a major switch of developmental genes expression, while NCBP1 and eIF4A3 depletions regulate the expression of genes involved in metabolism, chromatin remodeling and development. Further analysis highlighted a transcriptional and post-transcriptional regulation of differentially expressed genes. Alternative Splicing (AS) were shown to be affected by both depletions. A tissue specific AS program was associated to each of the candidates and the consequences of these changes on mRNA quality control and protein synthesis will be described.Our results build a new idea regarding the role of Core Spliceosomal Factors in cell fate control trough the modulation of AS. This knowledge adds a new layer of gene expression control and will allow a better understanding of early development mechanisms and tissue diversity

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Wolf, Alexander. "Jmjd6 katalysiert Lysin-5-Hydroxylierungen an U2AF-65 und ist ein potentieller Regulator des Spleißprozesses." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-104005.

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Tari, Manel. "Etude du rôle des facteurs d'épissage à domaines UHM dans la régulation de l'épissage alternatif." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLE041.

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Les protéines U2AF65, CAPERα, PUF60 et SPF45 sont des facteurs d'épissage qui possèdent des domaines similaires appelés UHM et qui interagissent pendant les étapes précoces de l'épissage avec des protéines qui possèdent des domaines ULM, comme SF3b155. Par des approches biochimiques, nous avons mis en évidence la formation d'assemblages macromoléculaires par U2AF65 et CAPERα au contact du domaine multi-ULM de SF3b155. En diminuant les taux d'expression des facteurs d'épissage à domaines UHM avec des shRNA et en analysant par qPCR l'épissage de 65 exons cassette, nous avons identifié un rôle activateur de CAPERα, U2AF65 et PUF60 et un rôle répresseur de SPF45 dans l'épissage. Plus particulièrement, CAPERα et U2AF65 activent l'épissage des exons cassette présentant des séquences flanquantes en 5' riches en motifs polypyrimidine. De plus, ces séquences favorisent la formation des assemblages macromoléculaires de U2AF65 et CAPERα. Appuyés par ces résultats, nous proposons un modèle dans lequel des interactions multivalentes conduisent à la formation d'assemblages macromoléculaires par CAPERα et U2AF65 ; ces complexes ont une affinité particulière d'une part pour les séquences introniques riches en motifs polypyrimidine et d'autre part avec le domaine multi-ULM de SF3b155. L'ensemble de ces interactions favorise la reconnaissance des sites 3' d'épissage
U2AF65, CAPERα, PUF60 and SPF45 are splicing factors that hold similar domains called UHM that interact during the early splicing steps with ULM domains proteins, such as SF3b155. Using biochemical approaches, we highlighted the formation of macromolecular assemblies by U2AF65 and CAPERα in contact with the multi-ULM domain of SF3b155. The inhibition of the expression of the UHM splicing factors by shRNA, followed by a qPCR analysis of 65 cassette exons led us to identify an activating role of CAPERα, U2AF65 and PUF60 and a repressing role of SPF45 in splicing. Particularly, CAPERα and U2AF65 activate splicing of cassette exons presenting long pyrimidine-rich 5' flanking regions. Moreover, these regions favor the formation of macromolecular assemblies of U2AF65 and CAPERα. On the basis of these results, we propose a model in which multivalent interactions lead to CAPERα and U2AF65 macromolecular assemblies; these assemblies present a particular affinity on one hand for long pyrimidine-rich introns and on the other one for the multi-ULM domain of SF3b155. All these interactions promote 3' splice sites recognition

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Lopes, Pereira Patricia. "Analyse phénotypique de modèles murins monosomique et trisomique pour la région Abcgl-U2afl associée au chromosome 21 humain." Orléans, 2007. http://www.theses.fr/2007ORLE2056.

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Le syndrome de Down (SD) ou trisomie 21 (T21) est caractérisé par des anomalies morphologiques, des troubles cognitifs et moteurs associés à un retard mental. L’analyse génétique de cette pathologie nécessite le développement de modèles animaux. Afin de complémenter les modèles murins de T21 existant, notre laboratoire s’est attaché à créer de nouveaux modèles d’aneuploïdie des régions d’homologie au chromosome 21 humain. Mon travail de thèse à porté sur l’étude phénotypique de deux de ces modèles : les modèles Ms2Yah (monosomique) et Ts1Yah (trisomique) pour la région Abcg1-U2af1 (13 gènes), homologue à la partie télomérique du chromosome 21 humain. Des analyses préliminaires du transcriptome révèlent que les gènes de la région Abcg1-U2af1 sont globalement sous-exprimés d’un facteur de 0,5 dans le modèle monosomique et sur-exprimés de 1,5 dans le modèle de trisomie. Ces deux lignées se révèlent être de bons modèles d’étude de l’homocystéinurie, la concentration en homocystéine plasmatique chez ces souris étant liée au nombre de copies de la région d’aneuploïdie. Des analyses en cours suggèrent également une macrocytose chez les individus Ms2Yah. Une homocystéinurie et une macrocytose sont fréquentes chez les enfants et les adultes atteints du SD et seraient dues à une activité plus importante de la CBS dans ce syndrome. Enfin, un premier criblage comportemental révèle une force d’agrippement plus élevée et des troubles de l’habituation ou de la mémoire chez les individus de la lignée Ts1Yah. Ces deux modèles seront par la suite combinés avec les autres lignées aneuploïdes pour mieux comprendre les interactions génétiques en cause dans cette pathologie. Ces études devraient à terme conduire à l’identification des voies de signalisation perturbées chez les patients et permettre le développement de nouvelles approches thérapeutiques.

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McCaw, Patrick Schonleber 1964. "Recognition of the pyrimidine-tract of the pre-mRNA by U2AF and a novel splicing factor PUF60." Thesis, Massachusetts Institute of Technology, 1998. http://hdl.handle.net/1721.1/47566.

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Urban, Joshua Raymond. "Differential expression of for, fax, and U2Af orthologs among three termite castes of the termite, Reticulitermes flavipes (Isoptera: rhinotermitidae)." Thesis, Kansas State University, 2010. http://hdl.handle.net/2097/4645.

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Master of Science
Department of Entomology
Srinivas Kambhampati
Termites (Isoptera) are eusocial insects and exhibit highly complex eusocial behavior. Eusociality is characterized by the presence of castes (workers, soldiers, reproductives), polyphenisms (same genotype exhibiting multiple phenotypes), flexible developmental pathways, complex communication, cooperative brood care, construction and maintenance of complex nests, and division of labor. Previous studies on honey bees implicated several genes in caste-specific behavior; here, we investigate if orthologs of such genes are present in termites and if so, whether they are expressed differentially among the castes. A candidate gene approach using degenerate primers was used to amplify three candidate genes in the termite Reticulitermes flavipes. Quantitative real time PCR analysis revealed differential expression among termite workers, soldiers, and alates, with a general pattern of higher expression in alates. These results provide information on three novel genes in the termite R. flavipes.

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Marechal, Damien. "Implication de la région Abcg1-U2af1 dans le syndrome de Down : effets de doses de la région et rôle du gène Cbs dans les défauts de mémorisation." Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00856595.

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Le syndrome de Down (SD), ou Trisomie 21, est l'aneuploïdie la plus fréquente chez l'humain. Le désordre génomique est tel qu'aucun traitement unique ne peut pallier à tous les symptômes (retard mental, troubles moteurs...). C'est pourquoi l'utilisation de modèles murins permet d'étudier l'impact de régions partielles du Hsa21 dans l'apparition des déficits. Mon projet de thèse s'est orienté sur un locus télomérique encadré par les gènes Abcg1 et U2af1. Mes recherches se sont focalisées sur deux modèles, Ts1Yah et Ms2Yah, dédiés à cette région. L'étude de ces lignées, combinées à d'autres modèles transgéniques, a montré la contribution de l'intervalle génique dans l'optimisation de l'apprentissage locomoteur. Dans un deuxième temps, le gène Cbs, candidat à la perte de fonction de mémoire, a permis de mettre en évidence un sauvetage fonctionnel dans une expérience à effets de doses. Cette découverte ouvre la voie à de nouvelles perspectives thérapeutiques.

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Foong, Louise Yuli. "Thiol reactive chemical probes for studying protein ion channel structure and the application of chemical probes to the study of U2AF, an essential RNA splicing factor." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ63599.pdf.

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Sánchez, Rico Carolina [Verfasser], Michael [Akademischer Betreuer] Sattler, Friedrich [Gutachter] Förster, Bernd [Gutachter] Reif, and Michael [Gutachter] Sattler. "Conformational Dynamics and Mechanisms of RNA Recognition by the Multidomain Splicing Factor U2AF / Carolina Sánchez Rico ; Gutachter: Friedrich Förster, Bernd Reif, Michael Sattler ; Betreuer: Michael Sattler." München : Universitätsbibliothek der TU München, 2017. http://d-nb.info/1152384074/34.

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Книги з теми "U2AF2"

Foong, Louise Yuli. Thiol reactive chemical probes for studying protein ion channel structure and the application of chemical probes to the study of U2AF, an essential RNA splicing factor. 2001.

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Bendari, Mounia, and Nisrine Khoubila. "Cytogenetic and Genetic Advances in Myelodysplasia Syndromes." In Cytogenetics - Classical and Molecular Strategies for Analysing Heredity Material. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.97112.

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Myelodysplasia syndromes (MDS) are defined by a heterogeneous group of myeloid malignancies characterized by peripheral blood cytopenia and dishematopoiesis and frequently progress to acute myeloid leukemia. Conventional karyotype has a crucial role in myelodysplastic syndrome (MDS) and is one of items of the International Prognostic Scoring System (IPSS) for patient risk stratification and treatment selection. Approximately 50–60% of cases of MDS present chromosomal abnormalities, like the deletions of chromosome 5q and 7q, trisomy 8, and complex karyotypes. New genomic technologies have been developted, like single-nucleotide polymorphism array and next-generation sequencing. They can identify the heterozygous deletions wich result in haplo-insufficient gene expression (e.g., CSNK1A1, DDX41 on chromosome 5, CUX1, LUC7L2, EZH2 on chromosome 7) involved in the pathogenesis of myelodysplasia syndromes. Genetic abnormalities are multiple, the most recurrent one are involved in the RNA splicing like SF3B1, SRSF2, U2AF1, ZRSR2, LUC7L2, and DDX41. Epigenetic modifications are also identified, such as histone modification as ASXL1, EZH2. Finally, it can be DNA methylation (e.g., TET2, DNMT3A, IDH1/IDH2). On this review we will summarize the most recent progress in molecular pathogenesis of MDS, and try to better understand the pathogenesis of the specific subgroups of MDS patients and applications of discovery of new genetic mutation in the development of new therapeutic.

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Тези доповідей конференцій з теми "U2AF2"

Laliotis, Georgios I., Evangelia Chavdoula, Maria D. Paraskevopoulou, Vollter Anastas, Ioannis Vlachos, Vasiliki Tarasslia, Artemis Hatzigeorgiou, et al. "Abstract 3649: Alternative RNA splicing of U2AF2, induced by AKT3-phosphorylated IWS1, promotes tumor growth, by activating a CDCA5-pERK positive feedback loop." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-3649.

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Laliotis, Georgios I., Evangelia Chavdoula, Maria D. Paraskevopoulou, Abdul Kaba, Alessandro La Ferlita, Vollter Anastas, Arturo Orlacchio, et al. "Abstract PO-011: IWS1 phosphorylation promotes tumor growth and predicts poor prognosis in EGFR mutant lung adenocarcinoma patients, through the epigenetic regulation of U2AF2 RNA splicing." In Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.epimetab20-po-011.

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Laliotis, Georgios I., Evangelia Chavdoula, Abdul Kaba, Alessandro La Ferlita, Vollter Anastas, Arturo Orlacchio, Lalit Sehgal, David P. Carbone, Vincenzo Coppola, and Philip N. Tsichlis. "Abstract PO010: The inhibition of IWS1 phosphorylation promotes genomic instability, the cGAS/STING pathway activation and PD-L1 levels, through the U2AF2 alternative RNA splicing and Sororin expression." In Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; October 19-20, 2020. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/2326-6074.tumimm20-po010.

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Laliotis, Georgios I., Adam D. Kenney, Evangelia Chavdoula, Arturo Orlacchio, Vollter Anastas, Alessandro La Ferlita, Abdul Kaba, et al. "Abstract PO088: Sensitivity of cancer cells to oncolytic viruses is defined by IWS1 phosphorylation dependent epigenetic regulation of U2AF2 splicing and nucleocytoplasmic export of type I IFN transcripts." In Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; October 19-20, 2020. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/2326-6074.tumimm20-po088.

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Laliotis, Georgios I., Adam D. Kenney, Arturo Orlacchio, Vincenzo Coppola, Jacob S. Yount, and Philip N. Tsichlis. "Abstract LB-183: Sensitivity of cancer cells to oncolytic viruses is defined by IWS1 phosphorylation dependent epigenetic regulation of U2AF2 splicing and nucleocytoplasmic export of type I IFN transcripts." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-lb-183.

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Qian, Jianfa, Lina Zhang, and Zhixiang Yin. "Type II code over F2 + uF2 + u2F2." In 2006 IEEE Information Theory Workshop - ITW '06 Chengdu. IEEE, 2006. http://dx.doi.org/10.1109/itw2.2006.323744.

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Shirai, Cara Lunn, James N. Ley, Brian White, Justin Tibbitts, Jin Shao, Matthew Ndonwi, Sanghyun Kim, Theresa Okeyo-Owuor, Timothy A. Graubert, and Matthew J. Walter. "Abstract B41: Mutant U2AF1 alters hematopoiesis and pre-mRNA splicing in transgenic mice." In Abstracts: AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; September 20-23, 2014; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1557-3265.hemmal14-b41.

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Shirai, Cara Lunn, James N. Ley, Brian White, Justin Tibbitts, Jin Shao, Matthew Ndonwi, Sanghyun Kim, Theresa Okeyo-Owuor, Timothy A. Graubert, and Matthew J. Walter. "Abstract PR06: Mutant U2AF1 alters hematopoiesis and pre-mRNA splicing in transgenic mice." In Abstracts: AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; September 20-23, 2014; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1557-3265.hemmal14-pr06.

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Wadugu, Brian A., Amanda Heard, Joseph Bradley, Matthew Ndonwi, and Matthew J. Walter. "Abstract 5112:U2af1, a spliceosome gene commonly mutated in MDS, is required for hematopoiesis." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-5112.

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Fei, Dennis, Hayley Motowski, Sameer Prasad, Jovian Yu, Robert Bradley, and Harold Varmus. "Abstract 4163: Molecular and physiological effects of splicing factor mutant U2AF1 in human lung cell lines and in mice." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4163.

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Звіти організацій з теми "U2AF2"

Walter, Matthew J. The Role of U2AF1 Mutations in the Pathogenesis of Myelodysplastic Syndromes. Fort Belvoir, VA: Defense Technical Information Center, October 2014. http://dx.doi.org/10.21236/ada613973.

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