title: Autophagy Regulates Chromatin Ubiquitination in DNA Damage Response through Elimination of SQSTM1/p62.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Luyao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Ran
authors.initials: R
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Wan
authors.initials: W
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Ke
authors.initials: K
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Systems Biomedicine and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
authors.forename: Jiadong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Hongquan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute for Cancer Genetics and Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.affiliation: 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; Center for Life Sciences, Peking-Tsinghua University, Beijing 100871, China; Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China. Electronic address: zhuweiguo@szu.edu.cn.
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhu
authors.affiliation: 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. Electronic address: zhaoying0812@bjmu.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D001343:Autophagy / Q000528:radiation effects; D000071183:Autophagy-Related Proteins / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000528:radiation effects; D045325:HCT116 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D034622:RNA Interference; D011836:Radiation Tolerance; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000528:radiation effects
chemical_list: D000071183:Autophagy-Related Proteins; D002843:Chromatin; D006657:Histones; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D044763:Ubiquitin-Conjugating Enzymes; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases; C455621:ATG3 protein, human
keywords: DNA damage; autophagy; histone ubiquitination; p62