RAD51通过双重调节泛素连接酶UHRF1，在DNA甲基转移酶1介导的基因组DNA维持甲基化过程中发挥关键作用。

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

作者信息

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

机构信息

Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, Zhejiang, China.

Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China.

出版信息

Proc Natl Acad Sci U S A. 2024 Dec 10;121(50):e2410119121. doi: 10.1073/pnas.2410119121. Epub 2024 Dec 2.

DOI:10.1073/pnas.2410119121

PMID:39621902

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11648659/

Abstract

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 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 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.

摘要

它与细菌的RecA蛋白相关，并且因其在DNA损伤的同源重组介导修复中的作用而最为人所知。在此，我们报告了它在基因组DNA维持甲基化中的意外功能，该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。它的缺陷导致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。其次，RAD51帮助UHRF1对组蛋白H3进行单泛素化以产生DNMT1招募信号。它直接结合H3，使UHRF1更易于结合并泛素化H3。破坏RAD51与H3之间的相互作用会减少DNMT1的招募以及基因组DNA维持甲基化的失败。因此，RAD51对UHRF1具有双重调节作用。这些结果确立了RAD51作为基因组和表观基因组完整性守护者的地位。