RAD51 plays critical roles in DNMT1-mediated maintenance methylation of genomic DNA by dually regulating the ubiquitin ligase UHRF1

IF 9.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2024-12-02 DOI:10.1073/pnas.2410119121

Guangxue Liu, Kaiyan Huang, Shiyao Liu, Yali Xie, Jinyan Huang, Tingbo Liang, Pumin Zhang

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Abstract

RAD51 is related to the bacterial RecA protein and is best known for its role in homologous recombination-mediated repair of DNA damage. Here, we report an unexpected function of RAD51 in the maintenance methylation of genomic DNA, a function that is separable from its role in homologous recombination. First, it acts as an inhibitor of the E3 ubiquitin ligase UHRF1. Deficiency in RAD51 causes excessive ubiquitination and degradation of the DNA methyltransferase DNMT1, leading to the loss of global DNA methylation. Second, RAD51 helps UHRF1 to monoubiquitinate histone H3 to generate DNMT1 recruiting signal. It binds H3 directly, enabling UHRF1 to bind and ubiquitinate H3 more readily. Disrupting the interaction between RAD51 and H3 diminishes DNMT1 recruitment and the failure of maintenance methylation of genomic DNA. Thus, RAD51 dually regulates UHRF1. These results establish RAD51 as a guardian of the integrity of both the genome and the epigenome.

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RAD51通过双调控泛素连接酶UHRF1，在dnmt1介导的基因组DNA维持甲基化中发挥关键作用

RAD51与细菌的RecA蛋白有关，并以其在同源重组介导的DNA损伤修复中的作用而闻名。在这里，我们报道了RAD51在维持基因组DNA甲基化中的一个意想不到的功能，这个功能与其在同源重组中的作用是可分离的。首先，它作为E3泛素连接酶UHRF1的抑制剂。缺乏RAD51会导致DNA甲基转移酶DNMT1的过度泛素化和降解，导致整体DNA甲基化的丧失。第二，RAD51帮助UHRF1单泛素化组蛋白H3产生DNMT1募集信号。它直接结合H3，使UHRF1更容易结合并泛素化H3。破坏RAD51和H3之间的相互作用会减少DNMT1的募集和基因组DNA维持甲基化的失败。因此，RAD51可以双重调控UHRF1。这些结果表明RAD51是基因组和表观基因组完整性的守护者。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Proceedings of the National Academy of Sciences of the United States of America 综合性期刊-综合性期刊

CiteScore

19.00

自引率

0.90%

发文量

3575

审稿时长

2.5 months

期刊介绍： The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.