LINE1 RNA demethylation sensitizes cancer cells to PARPi through global chromatin remodeling

BACKGROUND: Repression of DNA damage repair by PARP inhibitors (PARPi) has shown great efficacy in cancer treatment. However, therapy resistance remains a significant clinical challenge. RESULTS: A on L1 RNAs increases H3K9me3 levels, leading to reduced chromatin accessibility. This, in turn, inhibits DNA end resection at damage sites and prevents PARP1 dissociation, ultimately impairing homologous recombination repair and enhancing tumor sensitivity to PARPi. CONCLUSIONS: A that governs the DNA damage repair response, providing a potential strategy of targeting METTL3 in combination with PARPi for cancer therapy.