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: Here, we demonstrate that the N6-methyladenosine (m6A) modification of long interspersed nucleotide element-1 (LINE1, or L1) facilitates DNA damage repair in cancer cells, whereas removal of L1 m6A modifications enhances the sensitivity of both BRCA-wild-type and BRCA-mutant cells to PARPi. Specifically, following olaparib treatment, METTL3 accumulates on chromatin at non-damage sites, which results in increased chromatin accessibility. Knockdown of METTL3 or removal of m6A 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: Our findings unveil a novel regulatory mechanism of L1 m6A that governs the DNA damage repair response, providing a potential strategy of targeting METTL3 in combination with PARPi for cancer therapy.