Structure and repair of replication-coupled DNA breaks-Reference-Cited by-同舟云学术

Structure and repair of replication-coupled DNA breaks

Published:2024-08-16 Issue:6710 Volume:385 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Pavani Raphael¹^ORCID,Tripathi Veenu¹,Vrtis Kyle B.²^ORCID,Zong Dali¹^ORCID,Chari Raj³^ORCID,Callen Elsa¹,Pankajam Ajith V.¹,Zhen Gang¹,Matos-Rodrigues Gabriel¹^ORCID,Yang Jiajie⁴,Wu Shuheng⁴,Reginato Giordano⁵^ORCID,Wu Wei⁴^ORCID,Cejka Petr⁵^ORCID,Walter Johannes C.²⁶^ORCID,Nussenzweig André¹^ORCID

Affiliation:

1. Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA.

2. Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.

3. Genome Modification Core, Frederick National Lab for Cancer Research, Frederick, MD, USA.

4. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.

5. Institute for Research in Biomedicine, Universita della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland.

6. Howard Hughes Medical Institute, Harvard University, Boston, MA, USA.

Abstract

Using CRISPR-Cas9 nicking enzymes, we examined the interaction between the replication machinery and single-strand breaks, one of the most common forms of endogenous DNA damage. We show that replication fork collapse at leading-strand nicks generates resected single-ended double-strand breaks (seDSBs) that are repaired by homologous recombination (HR). If these seDSBs are not promptly repaired, arrival of adjacent forks creates double-ended DSBs (deDSBs), which could drive genomic scarring in HR-deficient cancers. deDSBs can also be generated directly when the replication fork bypasses lagging-strand nicks. Unlike deDSBs produced independently of replication, end resection at nick-induced seDSBs and deDSBs is BRCA1-independent. Nevertheless, BRCA1 antagonizes 53BP1 suppression of RAD51 filament formation. These results highlight distinctive mechanisms that maintain replication fork stability.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.ado3867

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