ArticleScience advances2024
Cancer-associated DNA hypermethylation of Polycomb targets requires DNMT3A dual recognition of histone H2AK119 ubiquitination and the nucleosome acidic patch.
Article in Science advances, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- A progeria syndrome links DNA hypermethylation to age-related pathology.Nature genetics · 2026Article
- Chromatin binding and N-terminal domains of DNMT3B1 confer specificity for developmentally regulated CpG island methylation.Genes & development · 2026Article
- Epigenetic modifications in cancer drug resistance: molecular mechanisms and therapeutic interventions.Molecular biomedicine · 2026Review
- DNMT1 loss leads to hypermethylation of a subset of late replicating domains by DNMT3A.PLoS genetics · 2026Article
- Mechanisms of DNA methyltransferase 3A1-mediated DNA methylation of nucleosomes.The Journal of biological chemistry · 2026Article
- Nucleosome spacing regulates linker methylation by DNMT3A2/3B3.Molecular cell · 2026Article
- A role of protein conformational dynamics in mammalian DNA methylation.Structural dynamics (Melville, N.Y.) · 2026Review
- Structural insight into hierarchical DNMT3A autoinhibition and its dysregulation in disease.Nature communications · 2026Article
- Mono-ubiquitination of histone H2A lysine 119 (H2AK119Ub): its multifaceted role in biology and implication in diseases.MedScience · 2026Review
- Mechanisms of DNMT3A-3L-mediated de novo DNA methylation on chromatin.Nature structural & molecular biology · 2026Article
- Pan-cancer 3D genomic analysis revealed extremely long Polycomb loops as the biomarker for sensitivity to Polycomb inhibition.bioRxiv : the preprint server for biology · 2025Article
- Nucleosome context regulates chromatin reader preference.Nucleic acids research · 2025Article
- The N-terminal region of DNMT3A engages the nucleosome surface to aid chromatin recruitment.EMBO reports · 2024Article
- Using human disease mutations to understand de novo DNA methyltransferase function.Biochemical Society transactions · 2024Review
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Abstract
During tumor development, promoter CpG islands that are normally silenced by Polycomb repressive complexes (PRCs) become DNA-hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) [DNMT(s)] catalyze CpG methylation at PRC-regulated regions remains unclear. Here, we report a cryo-electron microscopy structure of the DNMT3A long isoform (DNMT3A1) amino-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine-119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 amino terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Further, aberrant redistribution of DNMT3A1 to Polycomb target genes recapitulates the cancer-associated DNA hypermethylation signature and inhibits their transcriptional activation during cell differentiation. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for mediating promoter CpG island DNA hypermethylation, a major molecular hallmark of cancer.
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