Cancer-associated DNA Hypermethylation of Polycomb Targets Requires DNMT3A Dual Recognition of Histone H2AK119 Ubiquitination and the Nucleosome Acidic Patch.

A preprint abstract from biorxiv.org discusses the molecular mechanism behind the DNA hypermethylation of promoter CpG islands (CGIs) in cancer. The study focuses on the DNMT3A long isoform (DNMT3A1) and its interaction with a nucleosome carrying PRC1-mediated histone H2A lysine 119 monoubiquitination (H2AK119Ub). The researchers identify regions within the DNMT3A1 N-terminus that bind H2AK119Ub and the nucleosome acidic patch, and demonstrate that this interaction is necessary for effective engagement with H2AK119Ub-modified chromatin in cells. Aberrant redistribution of DNMT3A1 to Polycomb target genes inhibits their transcriptional activation during cell differentiation and leads to the cancer-associated DNA hypermethylation signature. The study highlights a critical binding interface that counteracts promoter CGI DNA hypermethylation, a major hallmark of cancer. [Extracted from the article]