Journal articles: '53BP1'

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Thukral, S. K., G. C. Blain, K. K. Chang, and S. Fields. "Distinct residues of human p53 implicated in binding to DNA, simian virus 40 large T antigen, 53BP1, and 53BP2." Molecular and Cellular Biology 14, no. 12 (December 1994): 8315–21. http://dx.doi.org/10.1128/mcb.14.12.8315-8321.1994.

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We identified a minimal domain of human p53 required for the transactivation of a p53 response element in Saccharomyces cerevisiae. This domain contains the central region of p53 sufficient for specific DNA binding, which colocalizes with the region responsible for binding simian virus 40 large T antigen, 53BP1, and 53BP2. Thirty amino acid positions, including natural mutational hot spots (R175, R213, R248, R249, and R273), in the minimal DNA-binding domain were mutated by alanine substitution. Alanine substitutions at positions R213, R248, R249, D281, R282, R283, E286, and N288 affected transactivation but allowed binding to at least one of the three interacting proteins; these amino acids may be involved in amino acid-base pair contacts. Surprisingly, alanine substitution at the mutational hot spot R175 did not affect DNA binding, transactivation, or T-antigen binding, although it nearly eliminated binding to 53BP1 and 53BP2. Mutation of H168 significantly affected only T-antigen binding, and mutation of E285 affected only 53BP1 binding. Thus, we implicate specific residues of p53 in different DNA and protein interactions.

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Thukral, S. K., G. C. Blain, K. K. Chang, and S. Fields. "Distinct residues of human p53 implicated in binding to DNA, simian virus 40 large T antigen, 53BP1, and 53BP2." Molecular and Cellular Biology 14, no. 12 (December 1994): 8315–21. http://dx.doi.org/10.1128/mcb.14.12.8315.

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We identified a minimal domain of human p53 required for the transactivation of a p53 response element in Saccharomyces cerevisiae. This domain contains the central region of p53 sufficient for specific DNA binding, which colocalizes with the region responsible for binding simian virus 40 large T antigen, 53BP1, and 53BP2. Thirty amino acid positions, including natural mutational hot spots (R175, R213, R248, R249, and R273), in the minimal DNA-binding domain were mutated by alanine substitution. Alanine substitutions at positions R213, R248, R249, D281, R282, R283, E286, and N288 affected transactivation but allowed binding to at least one of the three interacting proteins; these amino acids may be involved in amino acid-base pair contacts. Surprisingly, alanine substitution at the mutational hot spot R175 did not affect DNA binding, transactivation, or T-antigen binding, although it nearly eliminated binding to 53BP1 and 53BP2. Mutation of H168 significantly affected only T-antigen binding, and mutation of E285 affected only 53BP1 binding. Thus, we implicate specific residues of p53 in different DNA and protein interactions.

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Du Toit, Andrea. "Limiting 53BP1." Nature Reviews Molecular Cell Biology 14, no. 3 (February 13, 2013): 132. http://dx.doi.org/10.1038/nrm3532.

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Jullien, Denis, Paola Vagnarelli, William C. Earnshaw, and Yasuhisa Adachi. "Kinetochore localisation of the DNA damage response component 53BP1 during mitosis." Journal of Cell Science 115, no. 1 (January 1, 2002): 71–79. http://dx.doi.org/10.1242/jcs.115.1.71.

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53BP1 is a vertebrate BRCT motif protein, originally described as a direct interactor of p53, which has recently been shown to be implicated in the early response to DNA damage. Upon DNA damage, 53BP1 re-localises to discrete nuclear foci that are thought to represent sites of DNA lesions and becomes hyperphosphorylated. Several observations suggest that 53BP1 is a direct substrate for the ataxia telangiectasia mutated (ATM) kinase. So far, 53BP1 behaviour during mitosis has not been reported in detail. We have examined 53BP1 subcellular distribution in mitotic cells using several antibodies against 53BP1, and ectopic expression of GFP-tagged 53BP1. We found that 53BP1 significantly colocalised with CENP-E to kinetochores. 53BP1 is loaded to kinetochores in prophase, before CENP-E, and is released by mid-anaphase. By expressing various GFP-tagged 53BP1 truncations, the kinetochore binding domain has been mapped to a 380 residue portion of the protein that excludes the nuclear localisation signal and the BRCT motifs. Like many kinetochore-associated proteins involved in mitotic checkpoint signalling, more 53BP1 appears to accumulate on the kinetochores of chromosomes not aligned on the metaphase plate. Finally, we show that 53BP1 is hyperphosphorylated in mitotic cells, and undergoes an even higher level of phosphorylation in response to spindle disruption with colcemid. Our data suggest that 53BP1 may have a role in checkpoint signalling during mitosis and provide the evidence that DNA damage response machinery and mitotic checkpoint may share common molecular components.

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Ward, Irene M., Simone Difilippantonio, Kay Minn, Melissa D. Mueller, Julian R. Molina, Xiaochun Yu, Craig S. Frisk, Thomas Ried, Andre Nussenzweig, and Junjie Chen. "53BP1 Cooperates with p53 and Functions as a Haploinsufficient Tumor Suppressor in Mice." Molecular and Cellular Biology 25, no. 22 (November 15, 2005): 10079–86. http://dx.doi.org/10.1128/mcb.25.22.10079-10086.2005.

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ABSTRACT p53 binding protein 1 (53BP1) is a putative DNA damage sensor that accumulates at sites of double-strand breaks (DSBs) in a manner dependent on histone H2AX. Here we show that the loss of one or both copies of 53BP1 greatly accelerates lymphomagenesis in a p53-null background, suggesting that 53BP1 and p53 cooperate in tumor suppression. A subset of 53BP1−/− p53−/− lymphomas, like those in H2AX−/− p53−/− mice, were diploid and harbored clonal translocations involving antigen receptor loci, indicating misrepair of DSBs during V(D)J recombination as one cause of oncogenic transformation. Loss of a single 53BP1 allele compromised genomic stability and DSB repair, which could explain the susceptibility of 53BP1+/− mice to tumorigenesis. In addition to structural aberrations, there were high rates of chromosomal missegregation and accumulation of aneuploid cells in 53BP1−/− p53+/+ and 53BP1−/− p53−/− tumors as well as in primary 53BP1−/− splenocytes. We conclude that 53BP1 functions as a dosage-dependent caretaker that promotes genomic stability by a mechanism that preserves chromosome structure and number.

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Wang, Dejie, Jian Ma, Maria Victoria Botuyan, Gaofeng Cui, Yuqian Yan, Donglin Ding, Yingke Zhou, et al. "ATM-phosphorylated SPOP contributes to 53BP1 exclusion from chromatin during DNA replication." Science Advances 7, no. 25 (June 2021): eabd9208. http://dx.doi.org/10.1126/sciadv.abd9208.

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53BP1 activates nonhomologous end joining (NHEJ) and inhibits homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Dissociation of 53BP1 from DSBs and consequent activation of HR, a less error-prone pathway than NHEJ, helps maintain genome integrity during DNA replication; however, the underlying mechanisms are not fully understood. Here, we demonstrate that E3 ubiquitin ligase SPOP promotes HR during S phase of the cell cycle by excluding 53BP1 from DSBs. In response to DNA damage, ATM kinase–catalyzed phosphorylation of SPOP causes a conformational change in SPOP, revealed by x-ray crystal structures, that stabilizes its interaction with 53BP1. 53BP1-bound SPOP induces polyubiquitination of 53BP1, eliciting 53BP1 extraction from chromatin by a valosin-containing protein/p97 segregase complex. Our work shows that SPOP facilitates HR repair over NHEJ during DNA replication by contributing to 53BP1 removal from chromatin. Cancer-derived SPOP mutations block SPOP interaction with 53BP1, inducing HR defects and chromosomal instability.

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Ward, Irene M., Bernardo Reina-San-Martin, Alexandru Olaru, Kay Minn, Koji Tamada, Julie S. Lau, Marilia Cascalho, et al. "53BP1 is required for class switch recombination." Journal of Cell Biology 165, no. 4 (May 24, 2004): 459–64. http://dx.doi.org/10.1083/jcb.200403021.

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53BP1 participates early in the DNA damage response and is involved in cell cycle checkpoint control. Moreover, the phenotype of mice and cells deficient in 53BP1 suggests a defect in DNA repair (Ward et al., 2003b). Therefore, we asked whether or not 53BP1 would be required for the efficient repair of DNA double strand breaks. Our data indicate that homologous recombination by gene conversion does not depend on 53BP1. Moreover, 53BP1-deficient mice support normal V(D)J recombination, indicating that 53BP1 is not required for “classic” nonhomologous end joining. However, class switch recombination is severely impaired in the absence of 53BP1, suggesting that 53BP1 facilitates DNA end joining in a way that is not required or redundant for the efficient closing of RAG-induced strand breaks. These findings are similar to those observed in mice or cells deficient in the tumor suppressors ATM and H2AX, further suggesting that the functions of ATM, H2AX, and 53BP1 are closely linked.

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Rappold, Irene, Kuniyoshi Iwabuchi, Takayasu Date, and Junjie Chen. "Tumor Suppressor P53 Binding Protein 1 (53bp1) Is Involved in DNA Damage–Signaling Pathways." Journal of Cell Biology 153, no. 3 (April 30, 2001): 613–20. http://dx.doi.org/10.1083/jcb.153.3.613.

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The tumor suppressor p53 binding protein 1 (53BP1) binds to the DNA-binding domain of p53 and enhances p53-mediated transcriptional activation. 53BP1 contains two breast cancer susceptibility gene 1 COOH terminus (BRCT) motifs, which are present in several proteins involved in DNA repair and/or DNA damage–signaling pathways. Thus, we investigated the potential role of 53BP1 in DNA damage–signaling pathways. Here, we report that 53BP1 becomes hyperphosphorylated and forms discrete nuclear foci in response to DNA damage. These foci colocalize at all time points with phosphorylated H2AX (γ-H2AX), which has been previously demonstrated to localize at sites of DNA strand breaks. 53BP1 foci formation is not restricted to γ-radiation but is also detected in response to UV radiation as well as hydroxyurea, camptothecin, etoposide, and methylmethanesulfonate treatment. Several observations suggest that 53BP1 is regulated by ataxia telangiectasia mutated (ATM) after DNA damage. First, ATM-deficient cells show no 53BP1 hyperphosphorylation and reduced 53BP1 foci formation in response to γ-radiation compared with cells expressing wild-type ATM. Second, wortmannin treatment strongly inhibits γ-radiation–induced hyperphosphorylation and foci formation of 53BP1. Third, 53BP1 is readily phosphorylated by ATM in vitro. Taken together, these results suggest that 53BP1 is an ATM substrate that is involved early in the DNA damage–signaling pathways in mammalian cells.

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Salvador Moreno, Naike, Jing Liu, Karen M. Haas, Laurie L. Parker, Chaitali Chakraborty, Stephen J. Kron, Kurt Hodges, et al. "The nuclear structural protein NuMA is a negative regulator of 53BP1 in DNA double-strand break repair." Nucleic Acids Research 47, no. 6 (February 28, 2019): 2703–15. http://dx.doi.org/10.1093/nar/gkz138.

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Abstract P53-binding protein 1 (53BP1) mediates DNA repair pathway choice and promotes checkpoint activation. Chromatin marks induced by DNA double-strand breaks and recognized by 53BP1 enable focal accumulation of this multifunctional repair factor at damaged chromatin. Here, we unveil an additional level of regulation of 53BP1 outside repair foci. 53BP1 movements are constrained throughout the nucleoplasm and increase in response to DNA damage. 53BP1 interacts with the structural protein NuMA, which controls 53BP1 diffusion. This interaction, and colocalization between the two proteins in vitro and in breast tissues, is reduced after DNA damage. In cell lines and breast carcinoma NuMA prevents 53BP1 accumulation at DNA breaks, and high NuMA expression predicts better patient outcomes. Manipulating NuMA expression alters PARP inhibitor sensitivity of BRCA1-null cells, end-joining activity, and immunoglobulin class switching that rely on 53BP1. We propose a mechanism involving the sequestration of 53BP1 by NuMA in the absence of DNA damage. Such a mechanism may have evolved to disable repair functions and may be a decisive factor for tumor responses to genotoxic treatments.

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Tripathi, Vivek, Tirunelvely Nagarjuna, and Sagar Sengupta. "BLM helicase–dependent and –independent roles of 53BP1 during replication stress–mediated homologous recombination." Journal of Cell Biology 178, no. 1 (June 25, 2007): 9–14. http://dx.doi.org/10.1083/jcb.200610051.

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Mutations in BLM helicase cause Bloom syndrome, characterized by predisposition to all forms of cancer. We demonstrate that BLM, signal transducer 53BP1, and RAD51 interact during stalled replication. Interactions between the three proteins have functional consequences. Lack of 53BP1 decreases the cell survival and enhanced chromosomal aberration after replication arrest. 53BP1 exhibits both BLM-dependent and -independent anti-recombinogenic functions in human and mouse cells. Both BLM and 53BP1 abrogate endogenous RAD51 foci formation and disrupt RAD51 polymerization. Consequently, loss of BLM and 53BP1 synergistically enhances stress-dependent homologous recombination. These results provide evidence regarding the cooperation between BLM and 53BP1 during maintenance of genomic integrity.

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Ward, Irene M., Kay Minn, Jan van Deursen, and Junjie Chen. "p53 Binding Protein 53BP1 Is Required for DNA Damage Responses and Tumor Suppression in Mice." Molecular and Cellular Biology 23, no. 7 (April 1, 2003): 2556–63. http://dx.doi.org/10.1128/mcb.23.7.2556-2563.2003.

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ABSTRACT 53BP1 is a p53 binding protein of unknown function that binds to the central DNA-binding domain of p53. It relocates to the sites of DNA strand breaks in response to DNA damage and is a putative substrate of the ataxia telangiectasia-mutated (ATM) kinase. To study the biological role of 53BP1, we disrupted the 53BP1 gene in the mouse. We show that, similar to ATM−/− mice, 53BP1-deficient mice were growth retarded, immune deficient, radiation sensitive, and cancer prone. 53BP1−/− cells show a slight S-phase checkpoint defect and prolonged G2/M arrest after treatment with ionizing radiation. Moreover, 53BP1−/− cells feature a defective DNA damage response with impaired Chk2 activation. These data indicate that 53BP1 acts downstream of ATM and upstream of Chk2 in the DNA damage response pathway and is involved in tumor suppression.

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Bekker-Jensen, Simon, Claudia Lukas, Fredrik Melander, Jiri Bartek, and Jiri Lukas. "Dynamic assembly and sustained retention of 53BP1 at the sites of DNA damage are controlled by Mdc1/NFBD1." Journal of Cell Biology 170, no. 2 (July 11, 2005): 201–11. http://dx.doi.org/10.1083/jcb.200503043.

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53BP1 is a key component of the genome surveillance network activated by DNA double strand breaks (DSBs). Despite its known accumulation at the DSB sites, the spatiotemporal aspects of 53BP1 interaction with DSBs and the role of other DSB regulators in this process remain unclear. Here, we used real-time microscopy to study the DSB-induced redistribution of 53BP1 in living cells. We show that within minutes after DNA damage, 53BP1 becomes progressively, yet transiently, immobilized around the DSB-flanking chromatin. Quantitative imaging of single cells revealed that the assembly of 53BP1 at DSBs significantly lagged behind Mdc1/NFBD1, another DSB-interacting checkpoint mediator. Furthermore, short interfering RNA-mediated ablation of Mdc1/NFBD1 drastically impaired 53BP1 redistribution to DSBs and triggered premature dissociation of 53BP1 from these regions. Collectively, these in vivo measurements identify Mdc1/NFBD1 as a key upstream determinant of 53BP1's interaction with DSBs from its dynamic assembly at the DSB sites through sustained retention within the DSB-flanking chromatin up to the recovery from the checkpoint.

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Lu, Xiaopeng, Ming Tang, Qian Zhu, Qiaoyan Yang, Zhiming Li, Yantao Bao, Ge Liu, et al. "GLP-catalyzed H4K16me1 promotes 53BP1 recruitment to permit DNA damage repair and cell survival." Nucleic Acids Research 47, no. 21 (October 15, 2019): 10977–93. http://dx.doi.org/10.1093/nar/gkz897.

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Abstract The binding of p53-binding protein 1 (53BP1) to damaged chromatin is a critical event in non-homologous DNA end joining (NHEJ)-mediated DNA damage repair. Although several molecular pathways explaining how 53BP1 binds damaged chromatin have been described, the precise underlying mechanisms are still unclear. Here we report that a newly identified H4K16 monomethylation (H4K16me1) mark is involved in 53BP1 binding activity in the DNA damage response (DDR). During the DDR, H4K16me1 rapidly increases as a result of catalyzation by the histone methyltransferase G9a-like protein (GLP). H4K16me1 shows an increased interaction level with 53BP1, which is important for the timely recruitment of 53BP1 to DNA double-strand breaks. Differing from H4K16 acetylation, H4K16me1 enhances the 53BP1–H4K20me2 interaction at damaged chromatin. Consistently, GLP knockdown markedly attenuates 53BP1 foci formation, leading to impaired NHEJ-mediated repair and decreased cell survival. Together, these data support a novel axis of the DNA damage repair pathway based on H4K16me1 catalysis by GLP, which promotes 53BP1 recruitment to permit NHEJ-mediated DNA damage repair.

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Kawashita, Sayaka, Katsuya Matsuda, Hisayoshi Kondo, Yuriko Kitajima, Yuri Hasegawa, Takako Shimada, Michio Kitajima, Kiyonori Miura, Masahiro Nakashima, and Hideaki Masuzaki. "Significance of p53-Binding Protein 1 Nuclear Foci in Cervical Squamous Intraepithelial Lesions: Association With High-Risk Human Papillomavirus Infection and P16INK4a Expression." Cancer Control 27, no. 1 (January 1, 2020): 107327481990117. http://dx.doi.org/10.1177/1073274819901170.

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As p53-binding protein 1 (53BP1) localizes to the sites of DNA double-strand breaks and rapidly forms nuclear foci (NF), and its presence may be an indicator of endogenous genomic instability (GIN). We previously showed that 53BP1 NF in cervical cells increase with neoplastic progression, indicating the significance of 53BP1 expression for the estimation of malignant potential during cervical carcinogenesis. This study aimed to further elucidate the impact of 53BP1 expression as a biomarker for cervical squamous intraepithelial lesion (SIL). A total of 81 tissue samples, including 17 of normal cervical epithelium, 22 of cervical intraepithelial neoplasia (CIN) 1, 21 of CIN2, and 21 of CIN3, from patients positive for high-risk human papillomavirus (HR-HPV) were used for double-label immunofluorescence of 53BP1 and Ki-67/p16INK4a expression and HR-HPV in situ hybridization. We analyzed associations between 53BP1 expression type with parameters such as CIN grade, HR-HPV infection status, p16INK4a expression, and CIN prognosis. Expression type of 53BP1 was significantly associated with histological grade of CIN and HR-HPV in situ hybridization signal pattern ( P < .0001). There was a significant correlation between 53BP1 and p16INK4a expression levels ( r = .73, P < .0001). However, there was no association between 53BP1 expression type and CIN prognosis. We propose that 53BP1 expression type is a valuable biomarker for SIL, which can help estimate the grade and GIN of cervical lesions reflecting replication stress caused by the integration of HR-HPV to the host genome.

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West, Kirk L., Jessica L. Kelliher, Zhanzhan Xu, Liwei An, Megan R. Reed, Robert L. Eoff, Jiadong Wang, Michael S. Y. Huen, and Justin W. C. Leung. "LC8/DYNLL1 is a 53BP1 effector and regulates checkpoint activation." Nucleic Acids Research 47, no. 12 (April 15, 2019): 6236–49. http://dx.doi.org/10.1093/nar/gkz263.

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Abstract The tumor suppressor protein 53BP1 plays key roles in response to DNA double-strand breaks (DSBs) by serving as a master scaffold at the damaged chromatin. Current evidence indicates that 53BP1 assembles a cohort of DNA damage response (DDR) factors to distinctly execute its repertoire of DSB responses, including checkpoint activation and non-homologous end joining (NHEJ) repair. Here, we have uncovered LC8 (a.k.a. DYNLL1) as an important 53BP1 effector. We found that LC8 accumulates at laser-induced DNA damage tracks in a 53BP1-dependent manner and requires the canonical H2AX-MDC1-RNF8-RNF168 signal transduction cascade. Accordingly, genetic inactivation of LC8 or its interaction with 53BP1 resulted in checkpoint defects. Importantly, loss of LC8 alleviated the hypersensitivity of BRCA1-depleted cells to ionizing radiation and PARP inhibition, highlighting the 53BP1-LC8 module in counteracting BRCA1-dependent functions in the DDR. Together, these data establish LC8 as an important mediator of a subset of 53BP1-dependent DSB responses.

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Troullinaki, Maria, Ruben Garcia-Martin, David Sprott, Anne Klotzsche-von Ameln, Sylvia Grossklaus, Ioannis Mitroulis, Triantafyllos Chavakis, and Matina Economopoulou. "53BP1 Deficiency Promotes Pathological Neovascularization in Proliferative Retinopathy." Thrombosis and Haemostasis 119, no. 03 (January 8, 2019): 439–48. http://dx.doi.org/10.1055/s-0038-1676966.

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AbstractThe replication stress inflicted on retinal endothelial cells (ECs) in the context of hypoxia-induced pathological neovascularization during proliferative retinopathy is linked with activation of the deoxyribonucleic acid (DNA) repair response. Here, we studied the effect of deficiency of the DNA damage response adaptor 53BP1, which is an antagonist of homologous recombination (HR), in the context of proliferative retinopathy. In the model of retinopathy of prematurity (ROP), 53BP1-deficient mice displayed increased hypoxia-driven pathological neovascularization and tuft formation, accompanied by increased EC proliferation and reduced EC apoptosis, as compared with 53BP1-sufficient mice. In contrast, physiological retina angiogenesis was not affected by 53BP1 deficiency. Knockdown of 53BP1 in ECs in vitro also resulted in enhanced proliferation and reduced apoptosis of the cells under hypoxic conditions. Additionally, upon 53BP1 knockdown, ECs displayed increased HR rate in hypoxia. Consistently, treatment with an HR inhibitor reversed the hyper-proliferative angiogenic phenotype associated with 53BP1 deficiency in ROP. Thus, by unleashing HR, 53BP1 deletion increases pathological EC proliferation and neovascularization in the context of ROP. Our data shed light to a previously unknown interaction between the DNA repair response and pathological neovascularization in the retina.

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Chen, Yong, Chengyin Weng, Hui Zhang, Jianqun Sun, and Yawei Yuan. "A Direct Interaction Between P53-Binding Protein 1 and Minichromosome Maintenance Complex in Hepg2 Cells." Cellular Physiology and Biochemistry 47, no. 6 (2018): 2350–59. http://dx.doi.org/10.1159/000491607.

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Background/Aims: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. DNA damage repair in cancer cells is a promising approach for the treatment of cancers. We aimed to explore the potential interaction between p53-binding protein 1 (53BP1) and minichromosome maintenance (MCMs) proteins during DNA damage in human hepatoma HepG2 cells. Methods: The recombinant vectors of 53BP1 and MCMs with tags were constructed and transfected into HepG2 cells. Immunoprecipitation (IP) and mass spectrometry (MS) were performed to identify the possible interactions between 53BP1 and MCMs, and glutathione S-transferase (GST) pull-down assay was carried out to detect the direct interaction. Moreover, the expressions of MCM2 and MCM6 were suppressed by specific short hairpin RNAs (shRNAs), and then the chromatin fraction and foci formation of 53BP1 were examined under the condition of DNA damage. Results: The results showed that MCM2/3/5/6 was immunoprecipitated against the hemaglutinin (HA)-tagged 53BP1 in HepG2 cell nuclei. GST results revealed that there was a direct interaction between 53BP1 and MCMs complex. Moreover, the non-chromatin level of 53BP1 was significantly increased by down-regulation of MCM2 or MCM6, but was statistically decreased the chromatin level. Furthermore, we observed that knockdown of MCM2 or MCM6 could statistically inhibit the foci formation of 53BP1 in HepG2 cell nuclei upon bleomycin-induced DNA damage (P < 0.01). Conclusion: Our results suggest that there is a direct interaction between 53BP1 and MCMs, which is essential for 53BP1 chromatin fraction and foci formation in hepatoma HepG2 cells.

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Schochter, Fabienne, Kim Werner, Cäcilia Köstler, Anke Faul, Marie Tzschaschel, Barbara Alberter, Volkmar Müller, et al. "53BP1 Accumulation in Circulating Tumor Cells Identifies Chemotherapy-Responsive Metastatic Breast Cancer Patients." Cancers 12, no. 4 (April 9, 2020): 930. http://dx.doi.org/10.3390/cancers12040930.

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Evidence suggests that the DNA end-binding protein p53-binding protein 1 (53BP1) is down-regulated in subsets of breast cancer. Circulating tumor cells (CTCs) provide accessible “biopsy material” to track cell traits and functions and their alterations during treatment. Here, we prospectively monitored the 53BP1 status in CTCs from 67 metastatic breast cancer (MBC) patients with HER2- CTCs and known hormone receptor (HR) status of the primary tumor and/or metastases before, during, and at the end of chemotherapeutic treatment with Eribulin. Nuclear 53BP1 staining and genomic integrity were evaluated by immunocytochemical and whole-genome-amplification-based polymerase chain reaction (PCR) analysis, respectively. Comparative analysis of CTCs from patients with triple-negative and HR+ tumors revealed elevated 53BP1 levels in CTCs from patients with HR+ metastases, particularly following chemotherapeutic treatment. Differences in nuclear 53BP1 signals did not correlate with genomic integrity in CTCs at baseline or with nuclear γH2AX signals in MBC cell lines, indicating that 53BP1 detected features beyond DNA damage. Kaplan–Meier analysis revealed an increasing association between nuclear 53BP1-positivity and progression-free survival (PFS) during chemotherapy until the final visit. Our data suggest that 53BP1 detection in CTCs could be a useful marker to capture dynamic changes of chemotherapeutic responsiveness in triple-negative and HR+ MBC.

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Zgheib, Omar, Kristopher Pataky, Juergen Brugger, and Thanos D. Halazonetis. "An Oligomerized 53BP1 Tudor Domain Suffices for Recognition of DNA Double-Strand Breaks." Molecular and Cellular Biology 29, no. 4 (December 8, 2008): 1050–58. http://dx.doi.org/10.1128/mcb.01011-08.

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ABSTRACT 53BP1, the vertebrate ortholog of the budding yeast Rad9 and fission yeast Crb2/Rhp9 checkpoint proteins, is recruited rapidly to sites of DNA double-strand breaks (DSBs). A tandem tudor domain in human 53BP1 that recognizes methylated residues in the histone core is necessary, but not sufficient, for efficient recruitment. By analysis of deletion mutants, we identify here additional elements in 53BP1 that facilitate recognition of DNA DSBs. The first element corresponds to an independently folding oligomerization domain. Replacement of this domain with heterologous tetramerization domains preserves the ability of 53BP1 to recognize DNA DSBs. A second element is only about 15 amino acids long and appears to be a C-terminal extension of the tudor domain, rather than an independently functioning domain. Recruitment of 53BP1 to sites of DNA DSBs is facilitated by histone H2AX phosphorylation and ubiquitination. However, none of the 53BP1 domains/elements important for recruitment are known to bind phosphopeptides or ubiquitin, suggesting that histone phosphorylation and ubiquitination regulate 53BP1 recruitment to sites of DNA DSBs indirectly.

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Etourneaud, Laure, Angela Moussa, Emilie Rass, Diane Genet, Simon Willaume, Caroline Chabance-Okumura, Paul Wanschoor, et al. "Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage." Science Advances 7, no. 35 (August 2021): eabb3799. http://dx.doi.org/10.1126/sciadv.abb3799.

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Double-strand breaks (DSBs) are harmful lesions and a major cause of genome instability. Studies have suggested a link between the nuclear envelope and the DNA damage response. Here, we show that lamin B1, a major component of the nuclear envelope, interacts directly with 53BP1 protein, which plays a pivotal role in the DSB repair. This interaction is dissociated after DNA damage. Lamin B1 overexpression impedes 53BP1 recruitment to DNA damage sites and leads to a persistence of DNA damage, a defect in nonhomologous end joining and an increased sensitivity to DSBs. The identification of interactions domains between lamin B1 and 53BP1 allows us to demonstrate that the defect of 53BP1 recruitment and the DSB persistence upon lamin B1 overexpression are due to sequestration of 53BP1 by lamin B1. This study highlights lamin B1 as a factor controlling the recruitment of 53BP1 to DNA damage sites upon injury.

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Santos, Margarida Almeida, Michael S. Y. Huen, Mila Jankovic, Hua-Tang Chen, Andrés J. López-Contreras, Isaac A. Klein, Nancy Wong, et al. "Class switching and meiotic defects in mice lacking the E3 ubiquitin ligase RNF8." Journal of Experimental Medicine 207, no. 5 (April 12, 2010): 973–81. http://dx.doi.org/10.1084/jem.20092308.

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53BP1 is a well-known mediator of the cellular response to DNA damage. Two alternative mechanisms have been proposed to explain 53BP1’s interaction with DNA double-strand breaks (DSBs), one by binding to methylated histones and the other via an RNF8 E3 ligase–dependent ubiquitylation pathway. The formation of RNF8 and 53BP1 irradiation-induced foci are both dependent on histone H2AX. To evaluate the contribution of the RNF8-dependent pathway to 53BP1 function, we generated RNF8 knockout mice. We report that RNF8 deficiency results in defective class switch recombination (CSR) and accumulation of unresolved immunoglobulin heavy chain–associated DSBs. The CSR DSB repair defect is milder than that observed in the absence of 53BP1 but similar to that found in H2AX−/− mice. Moreover, similar to H2AX but different from 53BP1 deficiency, RNF8−/− males are sterile, and this is associated with defective ubiquitylation of the XY chromatin. Combined loss of H2AX and RNF8 does not cause further impairment in CSR, demonstrating that the two genes function epistatically. Importantly, although 53BP1 foci formation is RNF8 dependent, its binding to chromatin is preserved in the absence of RNF8. This suggests a two-step mechanism for 53BP1 association with chromatin in which constitutive loading is dependent on interactions with methylated histones, whereas DNA damage–inducible RNF8-dependent ubiquitylation allows its accumulation at damaged chromatin.

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Byrum, Andrea K., Denisse Carvajal-Maldonado, Miranda C. Mudge, David Valle-Garcia, Mona C. Majid, Romil Patel, Mathew E. Sowa, et al. "Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function." Journal of Cell Biology 218, no. 2 (January 2, 2019): 422–32. http://dx.doi.org/10.1083/jcb.201803003.

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53BP1 is a chromatin-associated protein that regulates the DNA damage response. In this study, we identify the TPX2/Aurora A heterodimer, nominally considered a mitotic kinase complex, as a novel binding partner of 53BP1. We find that TPX2/Aurora A plays a previously unrecognized role in DNA damage repair and replication fork stability by counteracting 53BP1 function. Loss of TPX2 or Aurora A compromises DNA end resection, BRCA1 and Rad51 recruitment, and homologous recombination. Furthermore, loss of TPX2 or Aurora A causes deprotection of stalled replication forks upon replication stress induction. This fork protection pathway counteracts MRE11 nuclease activity but functions in parallel to BRCA1. Strikingly, concurrent loss of 53BP1 rescues not only BRCA1/Rad51 recruitment but also the fork instability induced upon TPX2 loss. Our work suggests the presence of a feedback mechanism by which 53BP1 is regulated by a novel binding partner and uncovers a unique role for 53BP1 in replication fork stability.

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Sengupta, Sagar, Ana I. Robles, Steven P. Linke, Natasha I. Sinogeeva, Ran Zhang, Remy Pedeux, Irene M. Ward, et al. "Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest." Journal of Cell Biology 166, no. 6 (September 13, 2004): 801–13. http://dx.doi.org/10.1083/jcb.200405128.

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Bloom's syndrome is a rare autosomal recessive genetic disorder characterized by chromosomal aberrations, genetic instability, and cancer predisposition, all of which may be the result of abnormal signal transduction during DNA damage recognition. Here, we show that BLM is an intermediate responder to stalled DNA replication forks. BLM colocalized and physically interacted with the DNA damage response proteins 53BP1 and H2AX. Although BLM facilitated physical interaction between p53 and 53BP1, 53BP1 was required for efficient accumulation of both BLM and p53 at the sites of stalled replication. The accumulation of BLM/53BP1 foci and the physical interaction between them was independent of γ-H2AX. The active Chk1 kinase was essential for both the accurate focal colocalization of 53BP1 with BLM and the consequent stabilization of BLM. Once the ATR/Chk1- and 53BP1-mediated signal from replicational stress is received, BLM functions in multiple downstream repair processes, thereby fulfilling its role as a caretaker tumor suppressor.

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Anderson, Lindsay, Catherine Henderson, and Yasuhisa Adachi. "Phosphorylation and Rapid Relocalization of 53BP1 to Nuclear Foci upon DNA Damage." Molecular and Cellular Biology 21, no. 5 (March 1, 2001): 1719–29. http://dx.doi.org/10.1128/mcb.21.5.1719-1729.2001.

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ABSTRACT 53BP1 is a human BRCT protein that was originally identified as a p53-interacting protein by the Saccharomyces cerevisiaetwo-hybrid screen. Although the carboxyl-terminal BRCT domain shows similarity to Crb2, a DNA damage checkpoint protein in fission yeast, there is no evidence so far that implicates 53BP1 in the checkpoint. We have identified a Xenopus homologue of 53BP1 (XL53BP1). XL53BP1 is associated with chromatin and, in some cells, localized to a few large foci under normal conditions. Gamma-ray irradiation induces increased numbers of the nuclear foci in a dose-dependent manner. The damage-induced 53BP1 foci appear rapidly (in 30 min) after irradiation, and de novo protein synthesis is not required for this response. In human cells, 53BP1 foci colocalize with Mrel1 foci at later stages of the postirradiation period. XL53BP1 is hyperphosphorylated after X-ray irradiation, and inhibitors of ATM-related kinases delay the relocalization and reduce the phosphorylation of XL53BP1 in response to X-irradiation. In AT cells, which lack ATM kinase, the irradiation-induced responses of 53BP1 are similarly affected. These results suggest a role for 53BP1 in the DNA damage response and/or checkpoint control which may involve signaling of damage to p53.

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Shibata, Atsushi, and Penny A. Jeggo. "Roles for the DNA-PK complex and 53BP1 in protecting ends from resection during DNA double-strand break repair." Journal of Radiation Research 61, no. 5 (August 11, 2020): 718–26. http://dx.doi.org/10.1093/jrr/rraa053.

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Abstract p53-binding protein 1 (53BP1) exerts distinct impacts in different situations involving DNA double-strand break (DSB) rejoining. Here we focus on how 53BP1 impacts upon the repair of ionising radiation-induced DSBs (IR-DSBs) and how it interfaces with Ku, the DNA end-binding component of canonical non-homologous end-joining (c-NHEJ), the major DSB repair pathway in mammalian cells. We delineate three forms of IR-DSB repair: resection-independent c-NHEJ, which rejoins most IR-DSBs with fast kinetics in G1 and G2, and Artemis and resection-dependent c-NHEJ and homologous recombination (HR), which repair IR-DSBs with slow kinetics in G1 and G2 phase, respectively. The fast component of DSB repair after X-ray exposure occurs via c-NHEJ with normal kinetics in the absence of 53BP1. Ku is highly abundant and has avid DNA end-binding capacity which restricts DNA end-resection and promotes resection-independent c-NHEJ at most IR-DSBs. Thus, 53BP1 is largely dispensable for resection-independent c-NHEJ. In contrast, 53BP1 is essential for the process of rejoining IR-DSBs with slow kinetics. This role requires 53BP1’s breast cancer susceptibility gene I (BRCA1) C-terminal (BRCT) 2 domain, persistent ataxia telangiectasia mutated (ATM) activation and potentially relaxation of compacted chromatin at heterochromatic-DSBs. In distinction, 53BP1 inhibits resection-dependent IR-DSB repair in G1 and G2, and this resection-inhibitory function can be counteracted by BRCA1. We discuss a model whereby most IR-DSBs are rapidly repaired by 53BP1-independent and resection-independent c-NHEJ due to the ability of Ku to inhibit resection, but, if delayed, then resection in the presence of Ku is triggered, the 53BP1 barrier comes into force and BRCA1 counteraction is required for resection.

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An, Liwei, Chao Dong, Junshi Li, Jie Chen, Jingsong Yuan, Jun Huang, Kui Ming Chan, Cheng-han Yu, and Michael S. Y. Huen. "RNF169 limits 53BP1 deposition at DSBs to stimulate single-strand annealing repair." Proceedings of the National Academy of Sciences 115, no. 35 (August 13, 2018): E8286—E8295. http://dx.doi.org/10.1073/pnas.1804823115.

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Unrestrained 53BP1 activity at DNA double-strand breaks (DSBs) hampers DNA end resection and upsets DSB repair pathway choice. RNF169 acts as a molecular rheostat to limit 53BP1 deposition at DSBs, but how this fine balance translates to DSB repair control remains undefined. In striking contrast to 53BP1, ChIP analyses of AsiSI-induced DSBs unveiled that RNF169 exhibits robust accumulation at DNA end-proximal regions and preferentially targets resected, RPA-bound DSBs. Accordingly, we found that RNF169 promotes CtIP-dependent DSB resection and favors homology-mediated DSB repair, and further showed that RNF169 dose-dependently stimulates single-strand annealing repair, in part, by alleviating the 53BP1-imposed barrier to DSB end resection. Our results highlight the interplay of RNF169 with 53BP1 in fine-tuning choice of DSB repair pathways.

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Michelena, Jone, Stefania Pellegrino, Vincent Spegg, and Matthias Altmeyer. "Replicated chromatin curtails 53BP1 recruitment in BRCA1-proficient and BRCA1-deficient cells." Life Science Alliance 4, no. 6 (April 2, 2021): e202101023. http://dx.doi.org/10.26508/lsa.202101023.

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DNA double-strand breaks can be repaired by non-homologous end-joining or homologous recombination. Which pathway is used depends on the balance between the tumor suppressors 53BP1 and BRCA1 and on the availability of an undamaged template DNA for homology-directed repair. How cells switch from a 53BP1-dominated to a BRCA1-governed homologous recombination response as they progress through the cell cycle is incompletely understood. Here we reveal, using high-throughput microscopy and applying single cell normalization to control for increased genome size as cells replicate their DNA, that 53BP1 recruitment to damaged replicated chromatin is inefficient in both BRCA1-proficient and BRCA1-deficient cells. Our results substantiate a dual switch model from a 53BP1-dominated response in unreplicated chromatin to a BRCA1–BARD1–dominated response in replicated chromatin, in which replication-coupled dilution of 53BP1’s binding mark H4K20me2 functionally cooperates with BRCA1–BARD1–mediated suppression of 53BP1 binding. More generally, we suggest that appropriate normalization of single cell data, for example, to DNA content, provides additional layers of information, which can be critical for quantifying and interpreting cellular phenotypes.

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Foltánková, Veronika, Pavel Matula, Dmitry Sorokin, Stanislav Kozubek, and Eva Bártová. "Hybrid Detectors Improved Time-Lapse Confocal Microscopy of PML and 53BP1 Nuclear Body Colocalization in DNA Lesions." Microscopy and Microanalysis 19, no. 2 (February 15, 2013): 360–69. http://dx.doi.org/10.1017/s1431927612014353.

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AbstractWe used hybrid detectors (HyDs) to monitor the trajectories and interactions of promyelocytic leukemia (GFP-PML) nuclear bodies (NBs) and mCherry-53BP1-positive DNA lesions. 53BP1 protein accumulates in NBs that occur spontaneously in the genome or in γ-irradiation-induced foci. When we induced local DNA damage by ultraviolet irradiation, we also observed accumulation of 53BP1 proteins into discrete bodies, instead of the expected dispersed pattern. In comparison with photomultiplier tubes, which are used for standard analysis by confocal laser scanning microscopy, HyDs significantly eliminated photobleaching of GFP and mCherry fluorochromes during image acquisition. The low laser intensities used for HyD-based confocal analysis enabled us to observe NBs for the longer time periods, necessary for studies of the trajectories and interactions of PML and 53BP1 NBs. To further characterize protein interactions, we used resonance scanning and a novel bioinformatics approach to register and analyze the movements of individual PML and 53BP1 NBs. The combination of improved HyD-based confocal microscopy with a tailored bioinformatics approach enabled us to reveal damage-specific properties of PML and 53BP1 NBs.

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Grotsky, David A., Ignacio Gonzalez-Suarez, Anna Novell, Martin A. Neumann, Sree C. Yaddanapudi, Monica Croke, Montserrat Martinez-Alonso, et al. "BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells." Journal of Cell Biology 200, no. 2 (January 21, 2013): 187–202. http://dx.doi.org/10.1083/jcb.201204053.

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Loss of 53BP1 rescues BRCA1 deficiency and is associated with BRCA1-deficient and triple-negative breast cancers (TNBC) and with resistance to genotoxic drugs. The mechanisms responsible for decreased 53BP1 transcript and protein levels in tumors remain unknown. Here, we demonstrate that BRCA1 loss activates cathepsin L (CTSL)–mediated degradation of 53BP1. Activation of this pathway rescued homologous recombination repair and allowed BRCA1-deficient cells to bypass growth arrest. Importantly, depletion or inhibition of CTSL with vitamin D or specific inhibitors stabilized 53BP1 and increased genomic instability in response to radiation and poly(adenosine diphosphate–ribose) polymerase inhibitors, compromising proliferation. Analysis of human breast tumors identified nuclear CTSL as a positive biomarker for TNBC, which correlated inversely with 53BP1. Importantly, nuclear levels of CTSL, vitamin D receptor, and 53BP1 emerged as a novel triple biomarker signature for stratification of patients with BRCA1-mutated tumors and TNBC, with potential predictive value for drug response. We identify here a novel pathway with prospective relevance for diagnosis and customization of breast cancer therapy.

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Rass, Emilie, Simon Willaume, and Pascale Bertrand. "53BP1: Keeping It under Control, Even at a Distance from DNA Damage." Genes 13, no. 12 (December 16, 2022): 2390. http://dx.doi.org/10.3390/genes13122390.

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Double-strand breaks (DSBs) are toxic lesions that can be generated by exposure to genotoxic agents or during physiological processes, such as during V(D)J recombination. The repair of these DSBs is crucial to prevent genomic instability and to maintain cellular homeostasis. Two main pathways participate in repairing DSBs, namely, non-homologous end joining (NHEJ) and homologous recombination (HR). The P53-binding protein 1 (53BP1) plays a pivotal role in the choice of DSB repair mechanism, promotes checkpoint activation and preserves genome stability upon DSBs. By preventing DSB end resection, 53BP1 promotes NHEJ over HR. Nonetheless, the balance between DSB repair pathways remains crucial, as unscheduled NHEJ or HR events at different phases of the cell cycle may lead to genomic instability. Therefore, the recruitment of 53BP1 to chromatin is tightly regulated and has been widely studied. However, less is known about the mechanism regulating 53BP1 recruitment at a distance from the DNA damage. The present review focuses on the mechanism of 53BP1 recruitment to damage and on recent studies describing novel mechanisms keeping 53BP1 at a distance from DSBs.

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Rybanska, Ivana, Jeremy Chou, Mansi Prakash, David Huso, and Sonia Franco. "ATM and 53BP1 Function in Nonoverlapping Pathways to Suppress T Lineage Lymphomagenesis." Blood 120, no. 21 (November 16, 2012): 2374. http://dx.doi.org/10.1182/blood.v120.21.2374.2374.

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Abstract Abstract 2374 Background: In response to DNA double-strand breaks (DSB), mammalian cells activate the DNA Damage Response (DDR), a network of factors that promotes their detection, signaling and repair. Among DDR factors, the Ataxia-Telangiectasia Mutated (ATM) kinase and the 53BP1 adaptor localize to chromatin surrounding DSBs, where 53BP1 is thought to transduce a subset of ATM-dependent reactions. In addition, 53BP1 may have ATM-independent functions via its interactions with the MRE11/RAD50/NBS1 (MRN) complex and others to protect DNA ends from degradation and to promote synapsis of distant DSBs. Both ATM and 53BP1 are tumor suppressors in humans and mice, but whether the combined mutation may aggravate the DSB repair defect and/or accelerate oncogenesis in vivo is currently unknown. Objectives: 1) To generate a compound mouse model deficient for both ATM and 53BP1 and investigate their genetic interaction during growth and development; 2) To determine whether 53BP1 plays ATM-independent functions in DSB repair and cell cycle checkpoint activation in primary thymocytes; 3) To determine the effect of 53BP1 deficiency on the penetrance and latency of T cell lymphomas in ATM−/− mice. Design/Methods: We have generated 53BP1/ATM double knock out (DKO) mice and assessed the kinetics of DSB signaling and repair in primary thymocytes and mature B cells. We have also followed cohorts of DKO and control mice for tumor development and evaluated mechanisms of tumorigenesis using a combination of molecular, biochemical and cytogenetic approaches. Results: When compared to ATM−/− mice, DKO mice showed no differences in organismal growth and development, or in lymphoid differentiation. However, DKO mice developed T cell lymphomas with higher penetrance and at younger age than ATM−/− mice, and their survival was markedly reduced (p=0.0001; log-rank test). Like ATM−/− lymphomas, DKO lymphomas contained clonal translocations with breakpoints at the TCRα/δ locus and amplification of upstream DNA sequences, indicating that 53BP1 deficiency markedly accelerates the acquisition of oncogenic translocations in an ATM−/− background. In primary cells, loss of 53BP1 further increases the frequency of ionizing irradiation (IR)-induced chromosomal aberrations in ATM−/− cells. We will present a model for how 53BP1 actions at DSBs suppress genomic instability in ATM-deficient thymocytes, including its effects on checkpoint activation and DSB repair. Conclusion: Our studies in a mouse model of T cell lymphomagenesis suggest that mutations in 53BP1 and ATM may be nonmutually exclusive in human lymphomas. The combined mutation may define a subgroup of patients with more aggressive hematological malignancies, and may have implications for their response to therapy with DNA damaging agents. Disclosures: No relevant conflicts of interest to declare.

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Zhang, Fan, Lihong Lou, Bo Peng, Xiaotian Song, Ofer Reizes, Alexandru Almasan, and Zihua Gong. "Nudix Hydrolase NUDT16 Regulates 53BP1 Protein by Reversing 53BP1 ADP-Ribosylation." Cancer Research 80, no. 5 (January 7, 2020): 999–1010. http://dx.doi.org/10.1158/0008-5472.can-19-2205.

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Minter-Dykhouse, Katherine, Irene Ward, Michael S. Y. Huen, Junjie Chen, and Zhenkun Lou. "Distinct versus overlapping functions of MDC1 and 53BP1 in DNA damage response and tumorigenesis." Journal of Cell Biology 181, no. 5 (May 26, 2008): 727–35. http://dx.doi.org/10.1083/jcb.200801083.

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The importance of the DNA damage response (DDR) pathway in development, genomic stability, and tumor suppression is well recognized. Although 53BP1 and MDC1 have been recently identified as critical upstream mediators in the cellular response to DNA double-strand breaks, their relative hierarchy in the ataxia telangiectasia mutated (ATM) signaling cascade remains controversial. To investigate the divergent and potentially overlapping functions of MDC1 and 53BP1 in the ATM response pathway, we generated mice deficient for both genes. Unexpectedly, the loss of both MDC1 and 53BP1 neither significantly increases the severity of defects in DDR nor increases tumor incidence compared with the loss of MDC1 alone. We additionally show that MDC1 regulates 53BP1 foci formation and phosphorylation in response to DNA damage. These results suggest that MDC1 functions as an upstream regulator of 53BP1 in the DDR pathway and in tumor suppression.

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Schultz, Linda B., Nabil H. Chehab, Asra Malikzay, and Thanos D. Halazonetis. "P53 Binding Protein 1 (53bp1) Is an Early Participant in the Cellular Response to DNA Double-Strand Breaks." Journal of Cell Biology 151, no. 7 (December 25, 2000): 1381–90. http://dx.doi.org/10.1083/jcb.151.7.1381.

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p53 binding protein 1 (53BP1), a protein proposed to function as a transcriptional coactivator of the p53 tumor suppressor, has BRCT domains with high homology to the Saccharomyces cerevisiae Rad9p DNA damage checkpoint protein. To examine whether 53BP1 has a role in the cellular response to DNA damage, we probed its intracellular localization by immunofluorescence. In untreated primary cells and U2OS osteosarcoma cells, 53BP1 exhibited diffuse nuclear staining; whereas, within 5–15 min after exposure to ionizing radiation (IR), 53BP1 localized at discreet nuclear foci. We propose that these foci represent sites of processing of DNA double-strand breaks (DSBs), because they were induced by IR and chemicals that cause DSBs, but not by ultraviolet light; their peak number approximated the number of DSBs induced by IR and decreased over time with kinetics that parallel the rate of DNA repair; and they colocalized with IR-induced Mre11/NBS and γ-H2AX foci, which have been previously shown to localize at sites of DSBs. Formation of 53BP1 foci after irradiation was not dependent on ataxia-telangiectasia mutated (ATM), Nijmegen breakage syndrome (NBS1), or wild-type p53. Thus, the fast kinetics of 53BP1 focus formation after irradiation and the lack of dependency on ATM and NBS1 suggest that 53BP1 functions early in the cellular response to DNA DSBs.

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Nieto, Ainhoa, Makoto R. Hara, Victor Quereda, Wayne Grant, Vanessa Saunders, Kunhong Xiao, Patricia H. McDonald, and Derek R. Duckett. "βarrestin-1 regulates DNA repair by acting as an E3-ubiquitin ligase adaptor for 53BP1." Cell Death & Differentiation 27, no. 4 (September 10, 2019): 1200–1213. http://dx.doi.org/10.1038/s41418-019-0406-6.

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Abstract Cellular DNA is constantly under threat from internal and external insults, consequently multiple pathways have evolved to maintain chromosomal fidelity. Our previous studies revealed that chronic stress, mediated by continuous stimulation of the β2-adrenergic-βarrestin-1 signaling axis suppresses activity of the tumor suppressor p53 and impairs genomic integrity. In this pathway, βarrestin-1 (βarr1) acts as a molecular scaffold to promote the binding and degradation of p53 by the E3-ubiquitin ligase, MDM2. We sought to determine whether βarr1 plays additional roles in the repair of DNA damage. Here we demonstrate that in mice βarr1 interacts with p53-binding protein 1 (53BP1) with major consequences for the repair of DNA double-strand breaks. 53BP1 is a principle component of the DNA damage response, and when recruited to the site of double-strand breaks in DNA, 53BP1 plays an important role coordinating repair of these toxic lesions. Here, we report that βarr1 directs 53BP1 degradation by acting as a scaffold for the E3-ubiquitin ligase Rad18. Consequently, knockdown of βarr1 stabilizes 53BP1 augmenting the number of 53BP1 DNA damage repair foci following exposure to ionizing radiation. Accordingly, βarr1 loss leads to a marked increase in irradiation resistance both in cells and in vivo. Thus, βarr1 is an important regulator of double strand break repair, and disruption of the βarr1/53BP1 interaction offers an attractive strategy to protect cells against high levels of exposure to ionizing radiation.

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Jakl, Lukáš, Eva Marková, Lucia Koláriková, and Igor Belyaev. "Biodosimetry of Low Dose Ionizing Radiation Using DNA Repair Foci in Human Lymphocytes." Genes 11, no. 1 (January 4, 2020): 58. http://dx.doi.org/10.3390/genes11010058.

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Purpose: Ionizing radiation induced foci (IRIF) known also as DNA repair foci represent most sensitive endpoint for assessing DNA double strand breaks (DSB). IRIF are usually visualized and enumerated with the aid of fluorescence microscopy using antibodies to γH2AX and 53BP1. This study analyzed effect of low dose ionizing radiation on residual IRIF in human lymphocytes to the aim of potential biodosimetry and possible extrapolation of high-dose γH2AX/53BP1 effects to low doses and compared kinetics of DSB and IRIF. We also analyzed whether DNaseI, which is used for reducing of clumps, affects the IRIF level. Materials and Methods: The cryopreserved human lymphocytes from umbilical cord blood (UCB) were thawed with/without DNaseI, γ-irradiated at doses of 0, 5, 10, and 50 cGy and γH2AX/53BP1 foci were analyzed 30 min, 2 h, and 22 h post-irradiation using appropriate antibodies. We also analyzed kinetics of DSB using PFGE. Results: No significant difference was observed between data obtained by γH2AX foci evaluation in cells that were irradiated by low doses and data obtained by extrapolation from higher doses. Residual 53BP1 foci induced by low doses significantly outreached the data extrapolated from irradiation by higher doses. 53BP1 foci induced by low dose-radiation remain longer at DSB loci than foci induced by higher doses. There was no significant effect of DNaseI on DNA repair foci. Conclusions: Primary γH2AX, 53BP1 foci and their co-localization represent valuable markers for biodosimetry of low doses, but their usefulness is limited by short time window. Residual γH2AX and 53BP1 foci are more useful markers for biodosimetry in vitro. Effects of low doses can be extrapolated from high dose using γH2AX residual foci while γH2AX/53BP1 foci are valuable markers for evaluation of initial DSB induced by ionizing radiation. Residual IRIF induced by low doses persist longer time than those induced by higher doses.

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Wu, TingTing, Semo Jun, Eun-Ji Choi, Jiao Sun, Eun-Bi Yang, Hyun-Seo Lee, Sang-Yong Kim, et al. "53BP1-ACLY-SLBP-coordinated activation of replication-dependent histone biogenesis maintains genomic integrity." Nucleic Acids Research 50, no. 3 (January 17, 2022): 1465–83. http://dx.doi.org/10.1093/nar/gkab1300.

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Abstract p53-binding protein 1 (53BP1) regulates the DNA double-strand break (DSB) repair pathway and maintains genomic integrity. Here we found that 53BP1 functions as a molecular scaffold for the nucleoside diphosphate kinase-mediated phosphorylation of ATP-citrate lyase (ACLY) which enhances the ACLY activity. This functional association is critical for promoting global histone acetylation and subsequent transcriptome-wide alterations in gene expression. Specifically, expression of a replication-dependent histone biogenesis factor, stem-loop binding protein (SLBP), is dependent upon 53BP1-ACLY-controlled acetylation at the SLBP promoter. This chain of regulation events carried out by 53BP1, ACLY, and SLBP is crucial for both quantitative and qualitative histone biogenesis as well as for the preservation of genomic integrity. Collectively, our findings reveal a previously unknown role for 53BP1 in coordinating replication-dependent histone biogenesis and highlight a DNA repair-independent function in the maintenance of genomic stability through a regulatory network that includes ACLY and SLBP.

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Bailey, Sarah G., Elizabeth Verrall, Celine Schelcher, Alex Rhie, Aidan J. Doherty, and Alison J. Sinclair. "Functional Interaction between Epstein-Barr Virus Replication Protein Zta and Host DNA Damage Response Protein 53BP1." Journal of Virology 83, no. 21 (August 5, 2009): 11116–22. http://dx.doi.org/10.1128/jvi.00512-09.

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ABSTRACT Epstein-Barr virus (EBV; human herpesvirus 4) poses major clinical problems worldwide. Following primary infection, EBV enters a form of long-lived latency in B lymphocytes, expressing few viral genes, and it persists for the lifetime of the host with sporadic bursts of viral replication. The switch between latency and replication is governed by the action of a multifunctional viral protein Zta (also called BZLF1, ZEBRA, and Z). Using a global proteomic approach, we identified a host DNA damage repair protein that specifically interacts with Zta: 53BP1. 53BP1 is intimately connected with the ATM signal transduction pathway, which is activated during EBV replication. The interaction of 53BP1 with Zta requires the C-terminal ends of both proteins. A series of Zta mutants that show a wild-type ability to perform basic functions of Zta, such as dimer formation, interaction with DNA, and the transactivation of viral genes, were shown to have lost the ability to induce the viral lytic cycle. Each of these mutants also is compromised in the C-terminal region for interaction with 53BP1. In addition, the knockdown of 53BP1 expression reduced viral replication, suggesting that the association between Zta and 53BP1 is involved in the viral replication cycle.

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Orsburn, Benjamin, Beatriz Escudero, Mansi Prakash, Silvia Gesheva, Guosheng Liu, David L. Huso, and Sonia Franco. "Differential Requirement for H2AX and 53BP1 in Organismal Development and Genome Maintenance in the Absence of Poly(ADP)ribosyl Polymerase 1." Molecular and Cellular Biology 30, no. 10 (March 15, 2010): 2341–52. http://dx.doi.org/10.1128/mcb.00091-10.

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ABSTRACT Combined deficiencies of poly(ADP)ribosyl polymerase 1 (PARP1) and ataxia telangiectasia mutated (ATM) result in synthetic lethality and, in the mouse, early embryonic death. Here, we investigated the genetic requirements for this lethality via analysis of mice deficient for PARP1 and either of two ATM-regulated DNA damage response (DDR) factors: histone H2AX and 53BP1. We found that, like ATM, H2AX is essential for viability in a PARP1-deficient background. In contrast, deficiency for 53BP1 modestly exacerbates phenotypes of growth retardation, genomic instability, and organismal radiosensitivity observed in PARP1-deficient mice. To gain mechanistic insights into these different phenotypes, we examined roles for 53BP1 in the repair of replication-associated double-strand breaks (DSBs) in several cellular contexts. We show that 53BP1 is required for DNA-PKcs-dependent repair of hydroxyurea (HU)-induced DSBs but dispensable for RPA/RAD51-dependent DSB repair in the same setting. Moreover, repair of mitomycin C (MMC)-induced DSBs and sister chromatid exchanges (SCEs), two RAD51-dependent processes, are 53BP1 independent. Overall, our findings define 53BP1 as a main facilitator of nonhomologous end joining (NHEJ) during the S phase of the cell cycle, beyond highly specialized lymphocyte rearrangements. These findings have important implications for our understanding of the mechanisms whereby ATM-regulated DDR prevents human aging and cancer.

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Li, Zhendong, Jingxiao Bao, Yifei Qi, and John Z. H. Zhang. "Computational approaches to studying methylated H4K20 recognition by DNA repair factor 53BP1." Physical Chemistry Chemical Physics 22, no. 11 (2020): 6136–44. http://dx.doi.org/10.1039/c9cp05635a.

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Zgheib, Omar, Yentram Huyen, Richard A. DiTullio, Andrew Snyder, Monica Venere, Elena S. Stavridi, and Thanos D. Halazonetis. "ATM signaling and 53BP1." Radiotherapy and Oncology 76, no. 2 (August 2005): 119–22. http://dx.doi.org/10.1016/j.radonc.2005.06.026.

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Mirman, Zachary, and Titia de Lange. "53BP1: a DSB escort." Genes & Development 34, no. 1-2 (January 1, 2020): 7–23. http://dx.doi.org/10.1101/gad.333237.119.

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Soussi, Thierry, and Guido Kroemer. "TP53 and 53BP1 Reunited." Trends in Cell Biology 27, no. 5 (May 2017): 311–13. http://dx.doi.org/10.1016/j.tcb.2016.10.004.

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Zhang, Fan, Lihong Lou, Bo Peng, Xiaotian Song, Ofer Reizes, Alexandru Almasan, and Zihua Gong. "Correction: Nudix Hydrolase NUDT16 Regulates 53BP1 Protein by Reversing 53BP1 ADP-Ribosylation." Cancer Research 82, no. 15 (August 3, 2022): 2807. http://dx.doi.org/10.1158/0008-5472.can-22-1948.

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Yang, Linlin, Changxian Shen, Adriana Estrada-Bernal, Ryan Robb, Moumita Chatterjee, Nikhil Sebastian, Amy Webb, et al. "Oncogenic KRAS drives radioresistance through upregulation of NRF2-53BP1-mediated non-homologous end-joining repair." Nucleic Acids Research 49, no. 19 (October 4, 2021): 11067–82. http://dx.doi.org/10.1093/nar/gkab871.

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Abstract KRAS-activating mutations are oncogenic drivers and are correlated with radioresistance of multiple cancers, including colorectal cancer, but the underlying precise molecular mechanisms remain elusive. Herein we model the radiosensitivity of isogenic HCT116 and SW48 colorectal cancer cell lines bearing wild-type or various mutant KRAS isoforms. We demonstrate that KRAS mutations indeed lead to radioresistance accompanied by reduced radiotherapy-induced mitotic catastrophe and an accelerated release from G2/M arrest. Moreover, KRAS mutations result in increased DNA damage response and upregulation of 53BP1 with associated increased non-homologous end-joining (NHEJ) repair. Remarkably, KRAS mutations lead to activation of NRF2 antioxidant signaling to increase 53BP1 gene transcription. Furthermore, genetic silencing or pharmacological inhibition of KRAS, NRF2 or 53BP1 attenuates KRAS mutation-induced radioresistance, especially in G1 phase cells. These findings reveal an important role for a KRAS-induced NRF2-53BP1 axis in the DNA repair and survival of KRAS-mutant tumor cells after radiotherapy, and indicate that targeting NRF2, 53BP1 or NHEJ may represent novel strategies to selectively abrogate KRAS mutation-mediated radioresistance.

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Martínez, Paula, Juana M. Flores, and Maria A. Blasco. "53BP1 deficiency combined with telomere dysfunction activates ATR-dependent DNA damage response." Journal of Cell Biology 197, no. 2 (April 16, 2012): 283–300. http://dx.doi.org/10.1083/jcb.201110124.

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TRF1 protects mammalian telomeres from fusion and fragility. Depletion of TRF1 leads to telomere fusions as well as accumulation of γ-H2AX foci and activation of both the ataxia telangiectasia mutated (ATM)– and the ataxia telangiectasia and Rad3 related (ATR)–mediated deoxyribonucleic acid (DNA) damage response (DDR) pathways. 53BP1, which is also present at dysfunctional telomeres, is a target of ATM that accumulates at DNA double-strand breaks and favors nonhomologous end-joining (NHEJ) repair over ATM-dependent resection and homology-directed repair (homologous recombination [HR]). To address the role of 53BP1 at dysfunctional telomeres, we generated mice lacking TRF1 and 53BP1. 53BP1 deficiency significantly rescued telomere fusions in mouse embryonic fibroblasts (MEFs) lacking TRF1, but they showed evidence of a switch from the NHEJ- to HR-mediated repair of uncapped telomeres. Concomitantly, double-mutant MEFs showed evidence of hyperactivation of the ATR-dependent DDR. In intact mice, combined 53BP1/TRF1 deficiency in stratified epithelia resulted in earlier onset of DNA damage and increased CHK1 phosphorylation during embryonic development, leading to aggravation of skin phenotypes.

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Derlin, Thorsten, Natalia Bogdanova, Fiona Ohlendorf, Dhanya Ramachandran, Rudolf A. Werner, Tobias L. Ross, Hans Christiansen, Frank M. Bengel, and Christoph Henkenberens. "Assessment of γ-H2AX and 53BP1 Foci in Peripheral Blood Lymphocytes to Predict Subclinical Hematotoxicity and Response in Somatostatin Receptor-Targeted Radionuclide Therapy for Advanced Gastroenteropancreatic Neuroendocrine Tumors." Cancers 13, no. 7 (March 25, 2021): 1516. http://dx.doi.org/10.3390/cancers13071516.

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Background: We aimed to characterize γ-H2AX and 53BP1 foci formation in patients receiving somatostatin receptor-targeted radioligand therapy, and explored its role for predicting treatment-related hematotoxicity, and treatment response. Methods: A prospective analysis of double-strand break (DSB) markers was performed in 21 patients with advanced gastroenteropancreatic neuroendocrine tumors. γ-H2AX and 53BP1 foci formation were evaluated in peripheral blood lymphocytes (PBLs) at baseline, +1 h and +24 h after administration of 7.4 GBq (177Lu)Lu-DOTA-TATE. Hematotoxicity was evaluated using standard hematology. Therapy response was assessed using (68Ga)Ga-DOTA-TATE PET/CT before enrollment and after 2 cycles of PRRT according to the volumetric modification of RECIST 1.1. Results: DSB marker kinetics were heterogeneous among patients. Subclinical hematotoxicity was associated with γ-H2AX and 53BP1 foci formation (e.g., change in platelet count vs change in γ-H2AX+ cells between baseline and +1 h (r = −0.6080; p = 0.0045). Patients showing early development of new metastases had less γ-H2AX (p = 0.0125) and less 53BP1 foci per cell at +1 h (p = 0.0289), and demonstrated a distinct kinetic pattern with an absence of DSB marker decrease at +24 h (γ-H2AX: p = 0.0025; 53BP1: p = 0.0008). Conclusions: Assessment of γ-H2AX and 53BP1 foci formation in PBLs of patients receiving radioligand therapy may hold promise for predicting subclinical hematotoxicity and early treatment response.

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Roobol, Stefan J., Irene van den Bent, Wiggert A. van Cappellen, Tsion E. Abraham, Maarten W. Paul, Roland Kanaar, Adriaan B. Houtsmuller, Dik C. van Gent, and Jeroen Essers. "Comparison of High- and Low-LET Radiation-Induced DNA Double-Strand Break Processing in Living Cells." International Journal of Molecular Sciences 21, no. 18 (September 9, 2020): 6602. http://dx.doi.org/10.3390/ijms21186602.

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High-linear-energy-transfer (LET) radiation is more lethal than similar doses of low-LET radiation types, probably a result of the condensed energy deposition pattern of high-LET radiation. Here, we compare high-LET α-particle to low-LET X-ray irradiation and monitor double-strand break (DSB) processing. Live-cell microscopy was used to monitor DNA double-strand breaks (DSBs), marked by p53-binding protein 1 (53BP1). In addition, the accumulation of the endogenous 53BP1 and replication protein A (RPA) DSB processing proteins was analyzed by immunofluorescence. In contrast to α-particle-induced 53BP1 foci, X-ray-induced foci were resolved quickly and more dynamically as they showed an increase in 53BP1 protein accumulation and size. In addition, the number of individual 53BP1 and RPA foci was higher after X-ray irradiation, while focus intensity was higher after α-particle irradiation. Interestingly, 53BP1 foci induced by α-particles contained multiple RPA foci, suggesting multiple individual resection events, which was not observed after X-ray irradiation. We conclude that high-LET α-particles cause closely interspaced DSBs leading to high local concentrations of repair proteins. Our results point toward a change in DNA damage processing toward DNA end-resection and homologous recombination, possibly due to the depletion of soluble protein in the nucleoplasm. The combination of closely interspaced DSBs and perturbed DNA damage processing could be an explanation for the increased relative biological effectiveness (RBE) of high-LET α-particles compared to X-ray irradiation.

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Liu, Ting-Ting, Chien-Feng Li, Kien-Thiam Tan, Yi-Hua Jan, Pei-Hang Lee, Chih-Hao Huang, Shih-Chen Yu, Cheng-Feng Tsao, Jui-Chu Wang, and Hsuan-Ying Huang. "Characterization of Aberrations in DNA Damage Repair Pathways in Gastrointestinal Stromal Tumors: The Clinicopathologic Relevance of γH2AX and 53BP1 in Correlation with Heterozygous Deletions of CHEK2, BRCA2, and RB1." Cancers 14, no. 7 (March 31, 2022): 1787. http://dx.doi.org/10.3390/cancers14071787.

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Genetic aberrations involving DNA damage repair (DDR) remain underexplored in gastrointestinal stromal tumors (GISTs). We characterized DDR abnormalities using targeted next-generation sequencing and multiplex ligation-dependent probe amplification, and performed immunofluorescence (IF) and immunohistochemistry (IHC) analyses of γH2AX and 53BP1. Consistent with IF-validated nuclear co-localization, γH2AX and 53BP1 showed robust correlations in expression levels, as did both biomarkers between IF and IHC. Without recurrent pathogenic single-nucleotide variants, heterozygous deletions (HetDels) frequently targeted DNA damage-sensing genes, with CHEK2-HetDel being the most prevalent. Despite their chromosomal proximity, BRCA2 and RB1 were occasionally hit by HetDels and were seldom co-deleted. HetDels of CHEK2 and BRCA2 showed a preference for older age groups, while RB1-HetDel predominated in the non-gastric, high-risk, and 53BP1-overexpressing GISTs. Higher risk levels were consistently related to γ-H2AX or 53BP1 overexpression (all p < 0.01) in two validation cohorts, while only 53BP1 overexpression was associated with the deletion of KIT exon 11 (KITex11-del) among genotyped GISTs. Low expressers of dual biomarkers were shown by univariate analysis to have longer disease-free survival (p = 0.031). However, higher risk levels, epithelioid histology, and KITex11-del retained prognostic independence. Conclusively, IHC is a useful surrogate of laborious IF in the combined assessment of 53BP1 and γ-H2AX to identify potential DDR-defective GISTs, which were frequently aberrated by HetDels and a harbinger of progression.

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Ghodke, Indrajeet, Michaela Remisova, Audrey Furst, Sinan Kilic, Bernardo Reina-San-Martin, Anna R. Poetsch, Matthias Altmeyer, and Evi Soutoglou. "AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separation." Molecular Cell 81, no. 12 (June 2021): 2596–610. http://dx.doi.org/10.1016/j.molcel.2021.04.010.

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Journal articles on the topic '53BP1'

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