{Reference Type}: Journal Article
{Title}: Structure and repair of replication-coupled DNA breaks.
{Author}: Pavani R;Tripathi V;Vrtis KB;Zong D;Chari R;Callen E;Pankajam AV;Zhen G;Matos-Rodrigues G;Yang J;Wu S;Reginato G;Wu W;Cejka P;Walter JC;Nussenzweig A;
{Journal}: Science
{Volume}: 385
{Issue}: 6710
{Year}: 2024 Aug 16
{Factor}: 63.714
{DOI}: 10.1126/science.ado3867
{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.