Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Department of Medical Genetics, Center for Medical Genetics, Peking University Health Science Center, Beijing 100191, China.
Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Cell Rep. 2022 Jul 19;40(3):111116. doi: 10.1016/j.celrep.2022.111116.
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.
p62 是一种众所周知的自噬衔接蛋白，它在应对各种应激时发挥多种功能。在这里，我们报告了 p62 在碱基切除修复中的一个新功能，这与它已知的功能不同。p62 的缺失会损害碱基切除修复能力，并增加癌细胞对烷化剂和氧化剂的敏感性。在受到烷化剂和氧化剂的损伤时，p62 在细胞核中积累，被 hMOF 乙酰化，并被 SIRT7 去乙酰化，乙酰化的 p62 被招募到染色质上。富含染色质的 p62 直接与 BER 途径中的关键酶 APE1 相互作用，并促进其内切酶活性，从而促进 BER 和细胞存活。总之，我们的研究结果表明，p62 是 BER 的调节因子，并为将 p62 作为癌症治疗策略的靶点提供了进一步的依据。
