Acetylation of p62 regulates base excision repair through interaction with APE1

p62, a well-known adaptor of autophagy, plays multiple functions in response to various stresses. Here, we report a function for p62 in base excision repair that is distinct from its known functions. Loss of p62 impairs base excision repair capacity and increases the sensitivity of cancer cells to alkylating and oxidizing agents. In response to alkylative and oxidative damage, p62 is accumulated in the nucleus,acetylated by hMOF,and deacetylated by SIRT7, and acetylated p62 is recruited to chromatin. The chromatin-enriched p62 directly interacts with APE1, a key enzyme of the BER pathway, and promotes its endonuclease activity, which facilitates BER and cell survival. Collectively, our findings demonstrate that p62 is a regulator of BER and provide further rationale for targeting p62 as a cancer therapeutic strategy. [Display omitted] •hMOF acetylates p62 at K264 in response to alkylative and oxidative damage•SIRT7 deacetylates p62 at K264•p62 acetylation facilitates base excision repair pathway•p62 acetylation promotes APE1 chromatin association and enzymatic activity The autophagy receptor and substrate p62/SQSTM1 is regulated by complex post-translational modifications. Li et al. show that hMOF and SIRT7 dynamically regulate p62 acetylation at K264, which is crucial for base excision repair, by promoting APE1 chromatin recruitment and enzymatic activity.