Structure and repair of replication-coupled DNA breaks

• 成果类型: Article
• 署名作者: Pavani, Raphael; Tripathi, Veenu; Vrtis, Kyle B.; Zong, Dali; Chari, Raj; Callen, Elsa; Pankajam, Ajith V.; Zhen, Gang; Matos-Rodrigues, Gabriel; Yang, Jiajie; Wu, Shuheng; Reginato, Giordano; Wu, Wei; Cejka, Petr; Walter, Johannes C.; Nussenzweig, Andre
• 署名单位: National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Harvard University; Harvard Medical School; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; Universita della Svizzera Italiana; Harvard University; Howard Hughes Medical Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9174
• DOI: 10.1126/science.ado3867
• 发表日期: 2024-08-16
• 关键词: double-strand breaks; homology-directed repair; brca1 deficiency; recombination; 53bp1; resection; proteins; domain; forks; helicase

摘要

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.