%0 Journal Article
%T Structure and repair of replication-coupled DNA breaks.
%A Pavani R
%A Tripathi V
%A Vrtis KB
%A Zong D
%A Chari R
%A Callen E
%A Pankajam AV
%A Zhen G
%A Matos-Rodrigues G
%A Yang J
%A Wu S
%A Reginato G
%A Wu W
%A Cejka P
%A Walter JC
%A Nussenzweig A
%J Science
%V 385
%N 6710
%D 2024 Aug 16
%M 38900911
%F 63.714
%R 10.1126/science.ado3867
%X 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.