Poly-(ADP-ribose) serves as a scaffold for the methyltransferase METTL3/14 complex in the DNA damage response

PARP1, a crucial DNA break sensor, synthesizes poly-(ADP-ribose) (PAR), a nucleic acid that promotes the recruitment of DNA repair proteins. Emerging evidence highlights a role of RNA and RNA-binding proteins in DNA repair. Notably, the RNA-m6A methyltransferase complex METTL3/14 is implicated in repairing ultraviolet-induced DNA lesions. Here, we dissected the interplay between the two nucleic acids PAR and RNA and how METTL3/14 recruitment and m6A accumulation at laser-induced DNA lesions responds to PAR dynamics. In vitro, METTL3/14 recognized both PAR and RNA, yet PAR presence did not inhibit the methyltransferase complex's catalytic activity. Acute knock-out of METTL3 rendered cells sensitive to transcription-blocking DNA damage and resulted in defects in transcription recovery and transcription-coupled DNA repair. Furthermore, combining METTL3 and PARP inhibitors led to an enhanced antiproliferative effect on cancer cells. Future therapeutic avenues may thus leverage the interplay between the nucleic acids PAR and RNA.