Replicative gaps in DNA damage tolerance, genome instability, and cancer therapy - PubMed
5 hours ago
- #DNA damage tolerance
- #genome instability
- #cancer therapy
- Replicative single-stranded DNA gaps are key intermediates in cellular response to replication stress.
- Gaps form via polymerase-helicase uncoupling, impaired Okazaki fragment processing, PrimPol-mediated lesion bypass, and endogenous abasic site accumulation.
- Mechanisms to suppress, protect, and resolve gaps include RAD51/BRCA2 stabilization, PCNA modifications, and PARP1- and CST-dependent fill-in pathways.
- Persistent gaps contribute to fork degradation, genome instability, and innate immune activation.
- Gaps explain therapeutic vulnerabilities and resistance in cancer cells to PARP, Pol θ, and ATR inhibitors.
- Timely gap recognition and resolution are crucial for genome stability.