The Recombinase RAD51 Plays Critical Roles in the Maintenance Methylation of Genomic DNA by Promoting DNMT1 Stability and Recruitment

Here, we report a completely new and 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, a multifunction protein essential in DNA maintenance methylation. Deficiency in RAD51 causes excessive ubiquitination and subsequent proteasomal degradation of the DNA methyltransferase DNMT1, leading to the loss of global DNA methylation. Second, RAD51 binds histone H3 at residue R17, which promotes UHRF1 to bind and ubiquitinate H3 for the generation of DNMT1 recruitment signal. Disrupting the interaction between RAD51 and H3 diminishes DNMT1 recruitment and the failure of maintenance methylation of genomic DNA. These results shed new lights into the inner workings of the DNA maintenance methylation machinery, and establish RAD51 as a guardian of the integrity of both the genome and the epigenome.