生物
自噬
泛素
细胞生物学
DNA损伤
DNA修复
染色质
组蛋白
雷达51
基因组不稳定性
DNA
遗传学
基因
细胞凋亡
作者
Yanan Wang,Nan Zhang,Luyao Zhang,Ran Li,Wan Fu,Ke Ma,Xue Li,Lina Wang,Jiadong Wang,Hongquan Zhang,Wei Gu,Wei‐Guo Zhu,Ying Zhao
出处
期刊:Molecular Cell
[Elsevier]
日期:2016-07-01
卷期号:63 (1): 34-48
被引量:158
标识
DOI:10.1016/j.molcel.2016.05.027
摘要
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.
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