@article{1a4e7b88b9d8419b9bef86b15c6f78b0,
title = "ADP-ribosylation of histone variant H2AX promotes base excision repair",
abstract = "Optimal DNA damage response is associated with ADP-ribosylation of histones. However, the underlying molecular mechanism of DNA damage-induced histone ADP-ribosylation remains elusive. Herein, using unbiased mass spectrometry, we identify that glutamate residue 141 (E141) of variant histone H2AX is ADP-ribosylated following oxidative DNA damage. In-depth studies performed with wild-type H2AX and the ADP-ribosylation-deficient E141A mutant suggest that H2AX ADP-ribosylation plays a critical role in base excision repair (BER). Mechanistically, ADP-ribosylation on E141 mediates the recruitment of Neil3 glycosylase to the sites of DNA damage for BER. Moreover, loss of this ADP-ribosylation enhances serine-139 phosphorylation of H2AX (γH2AX) upon oxidative DNA damage and erroneously causes the accumulation of DNA double-strand break (DSB) response factors. Taken together, these results reveal that H2AX ADP-ribosylation not only facilitates BER repair, but also suppresses the γH2AX-mediated DSB response.",
keywords = "ADP-ribosylation, H2AX, PARP1, base excision repair",
author = "Qian Chen and Chunjing Bian and Xin Wang and Xiuhua Liu and {Ahmad Kassab}, Muzaffer and Yonghao Yu and Xiaochun Yu",
note = "Funding Information: We thank Dr. Justin W Leung at the University of Arkansas for Medical Sciences for sharing the U2OS H2AX knockout cells. We are thankful to Dr. Lan Li in the University of Harvard Medical School for the KillerRed plasmid and U2OS TRE cell line. This work was supported in part by grants from National Institutes of Health (CA132755 and CA130899 to X.Y., R01GM122932 and R35GM134883 to Y.Y.) and Welch Foundation (I‐1800 to Y.Y.). X.Y. is a recipient of Research Scholar Award from Pancreatic Cancer Action Network, The Henry and Marilyn Taub Foundation, and Tower Cancer Research Foundation. Research reported in this publication included work performed in the Integrative Genomics and Bioinformatics Core supported by the National Cancer Institute of the National Institutes of Health under grant number P30CA033572. Funding Information: We thank Dr. Justin W Leung at the University of Arkansas for Medical Sciences for sharing the U2OS H2AX knockout cells. We are thankful to Dr. Lan Li in the University of Harvard Medical School for the KillerRed plasmid and U2OS TRE cell line. This work was supported in part by grants from National Institutes of Health (CA132755 and CA130899 to X.Y., R01GM122932 and R35GM134883 to Y.Y.) and Welch Foundation (I-1800 to Y.Y.). X.Y. is a recipient of Research Scholar Award from Pancreatic Cancer Action Network, The Henry and Marilyn Taub Foundation, and Tower Cancer Research Foundation. Research reported in this publication included work performed in the Integrative Genomics and Bioinformatics Core supported by the National Cancer Institute of the National Institutes of Health under grant number P30CA033572. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2021",
month = jan,
day = "15",
doi = "10.15252/embj.2020104542",
language = "English (US)",
volume = "40",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "2",
}