LINE1 RNA demethylation represses chromatin accessibility and sensitizes cancer cells to blockage of DNA damage repair [ATAC-seq]

However, therapy resistance remains a significant clinical challenge. Here, we demonstrated 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, 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.