Destabilization of linker histone H1.2 is essential for ATM activation and DNA damage repair  被引量:4

Destabilization of linker histone H1.2 is essential for ATM activation and DNA damage repair

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作  者:Zhiming Li Yinglu Li Ming Tang Bin Peng Xiaopeng Lu Qiaoyan Yang Qian Zhu Tianyun Hou Meiting Li Chaohua Liu Lina Wang Xingzhi Xu Ying Zhao Haiying Wang Yang Yang Wei-Guo Zhu 

机构地区:[1]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 [2]Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China

出  处:《Cell Research》2018年第7期756-770,共15页细胞研究(英文版)

基  金:The authors are grateful to Dr. Tanya Paull (University of Texas, USA) and Dr. Fabrizio d'Adda di Fagagna (FIRC Institute of Molecular Oncology Foundation, Italy) for kindly providing the ATM plasmids; to Dr. Junjie Chen (MD Anderson Cancer Center, USA) for kindly providing NBSI KO HeLa cells and to Dr. Jessica Tamanini for editing the manuscript prior to submission. This study was supported by the National Key R&D Program of China (grant number 2017YFA0503900) and the National Natural Science Foundation of China (grant numbers 81621063, 81530074, 31570812 and 81720108027), and the Shenzhen Municipal Commission of Science and Technology Innovation (grant numbers JCYJ20160427104855100 and JCYJ201708180924S0901).

摘  要:Linker histone HI is a master regulator of higher order chromatin structure, but its involvement in the DNA damage response and repair is unclear. Here, we report that linker histone H1.2 is an essential regulator of ataxia telangiectasia mutated (ATM) activation. We show that H1.2 protects chromatin from aberrant ATM activation through direct interaction with the ATM HEAT repeat domain and inhibition of MRE11-RADSO-NBSI (MRN) complex-dependent ATM recruitment. Upon DNA damage, H1.2 undergoes rapid PARP1-dependent chromatin dissociation through poly-ADP-ribosylation (PARylation) of its C terminus and further proteasomal degradation. Inhibition of H1.2 displacement by PARPI depletion or an H1.2 PARylation-dead mutation compromises ATM activation and DNA damage repair, thus leading to impaired cell survival. Taken together, our findings suggest that linker histone H1.2 functions as a physiological barrier for ATM to target the chromatin, and PARylation-mediated active H1.2 turnover is required for robust ATM activation and DNA damage repair.

关 键 词:DNA damage response PolyADP-ribosylation 

分 类 号:Q523[生物学—生物化学] TN915.1[电子电信—通信与信息系统]

 

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