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Acetylation of 53BP1 dictates the DNA double strand break repair pathway

P53-binding protein 1 (53BP1) plays critical roles in DNA double strand break (DSB) repair by promoting non-homologous end joining (NHEJ), and loss of 53BP1 abolishes PARPi sensitivity in BRCA1-deficient cells by restoring homologous recombination (HR). 53BP1 is one of the proteins initially recruit...

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Autores principales: Guo, Xiang, Bai, Yongtai, Zhao, Meimei, Zhou, Mei, Shen, Qinjian, Yun, Cai-Hong, Zhang, Hongquan, Zhu, Wei-Guo, Wang, Jiadong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778472/
https://www.ncbi.nlm.nih.gov/pubmed/29190394
http://dx.doi.org/10.1093/nar/gkx1208
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author Guo, Xiang
Bai, Yongtai
Zhao, Meimei
Zhou, Mei
Shen, Qinjian
Yun, Cai-Hong
Zhang, Hongquan
Zhu, Wei-Guo
Wang, Jiadong
author_facet Guo, Xiang
Bai, Yongtai
Zhao, Meimei
Zhou, Mei
Shen, Qinjian
Yun, Cai-Hong
Zhang, Hongquan
Zhu, Wei-Guo
Wang, Jiadong
author_sort Guo, Xiang
collection PubMed
description P53-binding protein 1 (53BP1) plays critical roles in DNA double strand break (DSB) repair by promoting non-homologous end joining (NHEJ), and loss of 53BP1 abolishes PARPi sensitivity in BRCA1-deficient cells by restoring homologous recombination (HR). 53BP1 is one of the proteins initially recruited to sites of DSBs via recognition of H4K20me2 through the Tudor-UDR domain and H2AK15ub through the UDR motif. Although extensive studies have been conducted, it remains unclear how the post-translational modification of 53BP1 affects DSB repair pathway choice. Here, we identified 53BP1 as an acetylated protein and determined that acetylation of 53BP1 inhibit NHEJ and promote HR by negatively regulating 53BP1 recruitment to DSBs. Mechanistically, CBP-mediated acetylation of K1626/1628 in the UDR motif disrupted the interaction between 53BP1 and nucleosomes, subsequently blocking the recruitment of 53BP1 and its downstream factors PTIP and RIF1 to DSBs. Hyperacetylation of 53BP1, similar to depletion of 53BP1, restored PARPi resistance in BRCA1-deficient cells. Interestingly, 53BP1 acetylation was tightly regulated by HDAC2 to maintain balance between the HR and NHEJ pathways. Together, our results demonstrate that the acetylation status of 53BP1 plays a key role in its recruitment to DSBs and reveal how specific 53BP1 modification modulates the choice of DNA repair pathway.
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spelling pubmed-57784722018-01-30 Acetylation of 53BP1 dictates the DNA double strand break repair pathway Guo, Xiang Bai, Yongtai Zhao, Meimei Zhou, Mei Shen, Qinjian Yun, Cai-Hong Zhang, Hongquan Zhu, Wei-Guo Wang, Jiadong Nucleic Acids Res Genome Integrity, Repair and Replication P53-binding protein 1 (53BP1) plays critical roles in DNA double strand break (DSB) repair by promoting non-homologous end joining (NHEJ), and loss of 53BP1 abolishes PARPi sensitivity in BRCA1-deficient cells by restoring homologous recombination (HR). 53BP1 is one of the proteins initially recruited to sites of DSBs via recognition of H4K20me2 through the Tudor-UDR domain and H2AK15ub through the UDR motif. Although extensive studies have been conducted, it remains unclear how the post-translational modification of 53BP1 affects DSB repair pathway choice. Here, we identified 53BP1 as an acetylated protein and determined that acetylation of 53BP1 inhibit NHEJ and promote HR by negatively regulating 53BP1 recruitment to DSBs. Mechanistically, CBP-mediated acetylation of K1626/1628 in the UDR motif disrupted the interaction between 53BP1 and nucleosomes, subsequently blocking the recruitment of 53BP1 and its downstream factors PTIP and RIF1 to DSBs. Hyperacetylation of 53BP1, similar to depletion of 53BP1, restored PARPi resistance in BRCA1-deficient cells. Interestingly, 53BP1 acetylation was tightly regulated by HDAC2 to maintain balance between the HR and NHEJ pathways. Together, our results demonstrate that the acetylation status of 53BP1 plays a key role in its recruitment to DSBs and reveal how specific 53BP1 modification modulates the choice of DNA repair pathway. Oxford University Press 2018-01-25 2017-11-28 /pmc/articles/PMC5778472/ /pubmed/29190394 http://dx.doi.org/10.1093/nar/gkx1208 Text en © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Genome Integrity, Repair and Replication
Guo, Xiang
Bai, Yongtai
Zhao, Meimei
Zhou, Mei
Shen, Qinjian
Yun, Cai-Hong
Zhang, Hongquan
Zhu, Wei-Guo
Wang, Jiadong
Acetylation of 53BP1 dictates the DNA double strand break repair pathway
title Acetylation of 53BP1 dictates the DNA double strand break repair pathway
title_full Acetylation of 53BP1 dictates the DNA double strand break repair pathway
title_fullStr Acetylation of 53BP1 dictates the DNA double strand break repair pathway
title_full_unstemmed Acetylation of 53BP1 dictates the DNA double strand break repair pathway
title_short Acetylation of 53BP1 dictates the DNA double strand break repair pathway
title_sort acetylation of 53bp1 dictates the dna double strand break repair pathway
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778472/
https://www.ncbi.nlm.nih.gov/pubmed/29190394
http://dx.doi.org/10.1093/nar/gkx1208
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