Structure and repair of replication-coupled DNA breaks.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38900911.
- Also identified by DOI 10.1126/science.ado3867 and PMC identifier 11620331.
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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.
Medical subject headings
- BRCA1 Protein
- DNA Breaks, Double-Stranded
- DNA Breaks, Single-Stranded
- DNA Replication
- Rad51 Recombinase
- Tumor Suppressor p53-Binding Protein 1