Break-induced replication is activated to repair R-loop-associated double-strand breaks in SETX-deficient cells.

ABSTRACT: The primary role of break-induced replication (BIR) is to repair single-ended double-strand breaks (seDSBs) generated at broken replication forks and eroding telomeres. In this study, we demonstrated that when senataxin (SETX), an RNA/DNA helicase, is defective, hyper-recombination using the BIR mechanism is induced at R-loops/hybrid-accumulated double-ended DSBs (deDSBs), uncovering a role for BIR in the repair of R-loops/hybrids-associated deDSBs. Intriguingly, the loss of SETX not only triggers non-canonical hyper-end resection requiring RAD52 and XPF but also stalls Polα-primase-initiated end-fill DNA synthesis due to the accumulation of RNA/DNA hybrids on single-strand DNA (ssDNA) overhangs at deDSBs. This conflict between fill-in DNA synthesis and accumulated hybrids induces PCNA ubi

SUBMITTER: Wu T 

PROVIDER: S-EPMC12667547 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature