FTO suppresses DNA repair by inhibiting PARP1

Maintaining genomic integrity and faithful transmission of genetic information are essential for the survival and proliferation of cells and organisms. DNA damage, which threatens the integrity of the genome, is rapidly sensed and repaired by mechanisms collectively known as DNA damage response in cells. Using an unbiased quantitative proteomic approach, we revealed the interactome of an RNA demethylase FTO (fat mass and obesity-associated protein). We identified a direct interaction with the DNA damage sensor protein PARP1 (poly-ADP-ribose polymerase 1), which dissociates upon ultraviolet (UV) stimulation. FTO inhibits PARP1 catalytic activity and controls its clustering in the nucleolus. Loss of FTO enhances PARP1 enzymatic activity and the rate of PARP1 recruitment to DNA damage sites, thus accelerating DNA repair and, consequently, cell survival. Thus, our study establishes FTO as an endogenous negative regulator of PARP1 and the UV-induced DNA damage response, which has implications for the treatment options of various cancers.