Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Institute of Systems Biomedicine and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
Mol Cell. 2016 Jul 7;63(1):34-48. doi: 10.1016/j.molcel.2016.05.027. Epub 2016 Jun 23.
Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome, and loss of autophagy has been linked to increased genome instability. Here, we report that loss of autophagy is coupled to reduced histone H2A ubiquitination after DNA damage. p62/SQSTM1, which accumulates in autophagy-defective cells, directly binds to and inhibits nuclear RNF168, an E3 ligase essential for histone H2A ubiquitination and DNA damage responses. As a result, DNA repair proteins such as BRCA1, RAP80, and Rad51 cannot be recruited to the sites of DNA double-strand breaks (DSBs), which impairs DSB repair. Moreover, nuclear-localized p62 increased the sensitivity of tumor cells to radiation both in vitro and in vivo, and this required its interaction with RNF168. Our findings indicate that autophagy-deficiency-induced p62 accumulation results in inhibition of histone ubiquitination and highlight the complex relationship between autophagy and the DNA damage response.
自噬是一种将细胞质成分递送至溶酶体的细胞内降解系统，自噬的缺失与基因组不稳定性的增加有关。在这里，我们报告说，自噬缺失与 DNA 损伤后组蛋白 H2A 泛素化减少有关。p62/SQSTM1 在自噬缺陷细胞中积累，它直接结合并抑制核 RNF168，RNF168 是组蛋白 H2A 泛素化和 DNA 损伤反应所必需的 E3 连接酶。结果，DNA 修复蛋白，如 BRCA1、RAP80 和 Rad51，不能被招募到 DNA 双链断裂 (DSB) 的部位，从而损害 DSB 修复。此外，核定位的 p62 增加了肿瘤细胞对体外和体内辐射的敏感性，这需要其与 RNF168 的相互作用。我们的研究结果表明，自噬缺陷诱导的 p62 积累导致组蛋白泛素化抑制，并强调了自噬和 DNA 损伤反应之间的复杂关系。
