Microhomology-mediated end joining acts directly on replication forks to repair single-ended double-strand breaks - PubMed
6 hours ago
- #DNA repair
- #Cancer therapy
- #Replication stress
- Microhomology-mediated end joining (MMEJ) repairs single-ended double-strand breaks (seDSBs) at replication forks, termed fork-MMEJ.
- Fork-MMEJ operates preferentially on leading strands, functions independently of MRE11/CtIP-mediated end resection, and relies on RPA.
- Fork-MMEJ produces asymmetric deletion patterns, distinct from canonical MMEJ (cMMEJ) at replication-independent double-ended DSBs (deDSBs).
- ATR activation suppresses fork-MMEJ and promotes break-induced replication (BIR) as end resection proceeds.
- Combined inactivation of ATR and Polθ synergistically kills cancer cells under high replication stress with minimal toxicity to normal cells.
- The study provides insights into MMEJ mechanisms and suggests new strategies for cancer treatment.