fig1

Figure 1. UHRF1 acts as a multifunctional epigenetic regulator allowing crosstalk between DNA methylation and histone code. Its closed conformation from the binding of TTD and PBR can be activated by the binding of USP7 or PI5P (phosphatidylinositol 5-phosphate) to the PBR motif. (A) UHRF1 SRA domain identifies and recognizes hemimethylated sites of DNA. (B) PHD finger and TTD complex recognize methylated H3K9, which allows proper localization of DNMT1 on genomic loci. (C) RING finger function such as of ubiquitin E3 ligase to establish histone H3 ubiquitination at Lys23 and Lys18. (D) These ubiquitin markers are recognized by the DNMT1 RFS, promoting its localization to replication foci, which disrupts the interaction of RFTS and the catalytic domain of DNMT1. (E) This conformational change allows access of hemimethylated DNA to the catalytic domain of DNMT1, which results in a fully methylated DNA substrate. (F) The UBL domain of UHRF1 binds directly to DNMT1, further enhancing its enzymatic activity towards newly replicated chromatin. The mechanistic coordinated roles of both proteins ensure the faithful propagation of the DNA methylation patterns in DNA replication. Illustration was based on^[43,44].