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USP7通过减弱泛素化组蛋白依赖性DNMT1募集来负向调控整体DNA甲基化。

USP7 negatively controls global DNA methylation by attenuating ubiquitinated histone-dependent DNMT1 recruitment.

作者信息

Li Jialun, Wang Ruiping, Jin Jianyu, Han Mengmeng, Chen Zhaosu, Gao Yingying, Hu Xueli, Zhu Haijun, Gao Huifang, Lu Kongbin, Shao Yanjiao, Lyu Cong, Lai Weiyi, Li Pishun, Hu Guang, Li Jiwen, Li Dali, Wang Hailin, Wu Qihan, Wong Jiemin

机构信息

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241 China.

Joint Center for Translational Medicine, Fengxian District Central Hospital, 6600th Nanfeng Road, Fengxian District, Shanghai, 201499 China.

出版信息

Cell Discov. 2020 Aug 24;6:58. doi: 10.1038/s41421-020-00188-4. eCollection 2020.

DOI:10.1038/s41421-020-00188-4
PMID:32884836
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7445300/
Abstract

Previous studies have implicated an essential role for UHRF1-mediated histone H3 ubiquitination in recruiting DNMT1 to replication sites for DNA maintenance methylation during S phase of the cell cycle. However, the regulatory mechanism on UHRF1-mediated histone ubiquitination is not clear. Here we present evidence that UHRF1 and USP7 oppositely control ubiquitination of histones H3 and H2B in S phase of the cell cycle and that DNMT1 binds both ubiquitinated H3 and H2B. USP7 knockout markedly increased the levels of ubiquitinated H3 and H2B in S phase, the association of DNMT1 with replication sites and importantly, led to a progressive increase of global DNA methylation shown with increased cell passages. Using DNMT3A/DNMT3B/USP7 triple knockout cells and various DNA methylation analyses, we demonstrated that USP7 knockout led to an overall elevation of DNA methylation levels. Mechanistic study demonstrated that USP7 suppresses DNMT1 recruitment and DNA methylation through its deubiquitinase activity and the interaction with DNMT1. Altogether our study provides evidence that USP7 is a negative regulator of global DNA methylation and that USP7 protects the genome from excessive DNA methylation by attenuating histone ubiquitination-dependent DNMT1 recruitment.

摘要

先前的研究表明，UHRF1介导的组蛋白H3泛素化在细胞周期S期将DNMT1招募至复制位点以进行DNA维持甲基化过程中起着至关重要的作用。然而，UHRF1介导的组蛋白泛素化的调控机制尚不清楚。在此，我们提供证据表明，UHRF1和USP7在细胞周期S期对组蛋白H3和H2B的泛素化具有相反的调控作用，并且DNMT1与泛素化的H3和H2B均结合。USP7基因敲除显著增加了S期泛素化H3和H2B的水平、DNMT1与复制位点的关联，重要的是，随着细胞传代次数增加，导致整体DNA甲基化逐渐增加。使用DNMT3A/DNMT3B/USP7三重基因敲除细胞和各种DNA甲基化分析，我们证明USP7基因敲除导致DNA甲基化水平整体升高。机制研究表明，USP7通过其去泛素酶活性以及与DNMT1的相互作用抑制DNMT1招募和DNA甲基化。总之，我们的研究提供证据表明，USP7是整体DNA甲基化的负调控因子，并且USP7通过减弱组蛋白泛素化依赖性DNMT1招募来保护基因组免受过度的DNA甲基化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/8c9ee70a6e6d/41421_2020_188_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/fcf7e8b180ea/41421_2020_188_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/6006ead3595c/41421_2020_188_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/4cc813216f65/41421_2020_188_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/f71b1e3fd62d/41421_2020_188_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/f25d190a52cc/41421_2020_188_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/22f4f7e93101/41421_2020_188_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/8c9ee70a6e6d/41421_2020_188_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/fcf7e8b180ea/41421_2020_188_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/6006ead3595c/41421_2020_188_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/4cc813216f65/41421_2020_188_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/f71b1e3fd62d/41421_2020_188_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/f25d190a52cc/41421_2020_188_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/22f4f7e93101/41421_2020_188_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc39/7445300/8c9ee70a6e6d/41421_2020_188_Fig7_HTML.jpg

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