UHRF1-DNMT1 Cooperation in DNA Methylation Maintenance: Mechanistic and Oncogenic Insights

In mammalian cells, faithful propagation of DNA methylation patterns during S phase is crucial for epigenetic inheritance. The functional collaboration between DNA methyltransferase 1 (DNMT1) and ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is central to this process. According to structural research, the SRA domain of UHRF1 licenses maintenance methylation by identifying hemi-methylated CpG sites and extruding the methylated cytosine from the duplex via a base-flipping mechanism. Further research revealed that UHRF1 is a multidomain chromatin integrator rather than just a DNA sensor. Its tandem Tudor domain (TTD), plant homeodomain (PHD), ubiquitin-like domain (UBL), and RING finger work together to couple DNA replication, DNMT1 recruitment, and histone state. This pathway is further refined by ubiquitin sensing by the DNMT1 RFTS region and histone H3 ubiquitylation by UHRF1, which help explain how methylation patterns are replicated with high fidelity following replication. Aberrant UHRF1 expression in cancer is frequently linked to poor clinical outcomes, repression of tumor-suppressor networks, and epigenetic instability, particularly in proliferative epithelial malignancies. The idea that UHRF1 and DNMT1 accumulate in replication foci is supported by earlier reports, including findings in HeLa cells. This is consistent with a replication-coupled maintenance machinery functioning in living cancer cells. The structural logic of UHRF1 function, the mechanistic underpinnings of UHRF1-dependent DNMT1 activation, and the mounting evidence that the UHRF1–DNMT1 axis is both an actionable therapeutic vulnerability and a driver of malignant epigenetic maintenance are all covered in this review.