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RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity

The 53BP1-RIF1 pathway antagonizes resection of DNA broken ends and confers PARP inhibitor sensitivity on BRCA1-mutated tumors. However, it is unclear how this pathway suppresses initiation of resection. Here, we identify ASF1 as a partner of RIF1 via an interacting manner similar to its interaction...

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Autores principales: Feng, Sumin, Ma, Sai, Li, Kejiao, Gao, Shengxian, Ning, Shaokai, Shang, Jinfeng, Guo, Ruiyuan, Chen, Yingying, Blumenfeld, Britny, Simon, Itamar, Li, Qing, Guo, Rong, Xu, Dongyi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8854732/
https://www.ncbi.nlm.nih.gov/pubmed/35177609
http://dx.doi.org/10.1038/s41467-022-28588-y
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author Feng, Sumin
Ma, Sai
Li, Kejiao
Gao, Shengxian
Ning, Shaokai
Shang, Jinfeng
Guo, Ruiyuan
Chen, Yingying
Blumenfeld, Britny
Simon, Itamar
Li, Qing
Guo, Rong
Xu, Dongyi
author_facet Feng, Sumin
Ma, Sai
Li, Kejiao
Gao, Shengxian
Ning, Shaokai
Shang, Jinfeng
Guo, Ruiyuan
Chen, Yingying
Blumenfeld, Britny
Simon, Itamar
Li, Qing
Guo, Rong
Xu, Dongyi
author_sort Feng, Sumin
collection PubMed
description The 53BP1-RIF1 pathway antagonizes resection of DNA broken ends and confers PARP inhibitor sensitivity on BRCA1-mutated tumors. However, it is unclear how this pathway suppresses initiation of resection. Here, we identify ASF1 as a partner of RIF1 via an interacting manner similar to its interactions with histone chaperones CAF-1 and HIRA. ASF1 is recruited to distal chromatin flanking DNA breaks by 53BP1-RIF1 and promotes non-homologous end joining (NHEJ) using its histone chaperone activity. Epistasis analysis shows that ASF1 acts in the same NHEJ pathway as RIF1, but via a parallel pathway with the shieldin complex, which suppresses resection after initiation. Moreover, defects in end resection and homologous recombination (HR) in BRCA1-deficient cells are largely suppressed by ASF1 deficiency. Mechanistically, ASF1 compacts adjacent chromatin by heterochromatinization to protect broken DNA ends from BRCA1-mediated resection. Taken together, our findings identify a RIF1-ASF1 histone chaperone complex that promotes changes in high-order chromatin structure to stimulate the NHEJ pathway for DSB repair.
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spelling pubmed-88547322022-03-04 RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity Feng, Sumin Ma, Sai Li, Kejiao Gao, Shengxian Ning, Shaokai Shang, Jinfeng Guo, Ruiyuan Chen, Yingying Blumenfeld, Britny Simon, Itamar Li, Qing Guo, Rong Xu, Dongyi Nat Commun Article The 53BP1-RIF1 pathway antagonizes resection of DNA broken ends and confers PARP inhibitor sensitivity on BRCA1-mutated tumors. However, it is unclear how this pathway suppresses initiation of resection. Here, we identify ASF1 as a partner of RIF1 via an interacting manner similar to its interactions with histone chaperones CAF-1 and HIRA. ASF1 is recruited to distal chromatin flanking DNA breaks by 53BP1-RIF1 and promotes non-homologous end joining (NHEJ) using its histone chaperone activity. Epistasis analysis shows that ASF1 acts in the same NHEJ pathway as RIF1, but via a parallel pathway with the shieldin complex, which suppresses resection after initiation. Moreover, defects in end resection and homologous recombination (HR) in BRCA1-deficient cells are largely suppressed by ASF1 deficiency. Mechanistically, ASF1 compacts adjacent chromatin by heterochromatinization to protect broken DNA ends from BRCA1-mediated resection. Taken together, our findings identify a RIF1-ASF1 histone chaperone complex that promotes changes in high-order chromatin structure to stimulate the NHEJ pathway for DSB repair. Nature Publishing Group UK 2022-02-17 /pmc/articles/PMC8854732/ /pubmed/35177609 http://dx.doi.org/10.1038/s41467-022-28588-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Feng, Sumin
Ma, Sai
Li, Kejiao
Gao, Shengxian
Ning, Shaokai
Shang, Jinfeng
Guo, Ruiyuan
Chen, Yingying
Blumenfeld, Britny
Simon, Itamar
Li, Qing
Guo, Rong
Xu, Dongyi
RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity
title RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity
title_full RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity
title_fullStr RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity
title_full_unstemmed RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity
title_short RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity
title_sort rif1-asf1-mediated high-order chromatin structure safeguards genome integrity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8854732/
https://www.ncbi.nlm.nih.gov/pubmed/35177609
http://dx.doi.org/10.1038/s41467-022-28588-y
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