FTO suppresses DNA repair by inhibiting PARP1.

Maintaining genomic integrity and faithful transmission of genetic information is 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 the DNA damage response. The RNA demethylase FTO has been implicated in this process; however, the underlying mechanism by which FTO regulates DNA repair remains unclear. Here, we use an unbiased quantitative proteomic approach to identify the proximal interactome of endogenous FTO protein. Our results demonstrate a direct interaction with the DNA damage sensor protein PARP1, which dissociates upon ultraviolet 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, accelerating DNA repair and promoting cell survival. Interestingly, FTO regulates PARP1 function and DNA damage response independent of its catalytic activity. We conclude that FTO is an endogenous negative regulator of PARP1 and the DNA damage response in cells beyond its role as an RNA demethylase.