Cancer-associated DNA hypermethylation of Polycomb targets requires DNMT3A dual recognition of histone H2AK119 ubiquitination and the nucleosome acidic patch

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...

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Bibliographic Details
Published in:Science advances 2024-08, Vol.10 (35), p.eadp0975
Main Authors: Gretarsson, Kristjan H, Abini-Agbomson, Stephen, Gloor, Susan L, Weinberg, Daniel N, McCuiston, Jamie L, Kumary, Vishnu Udayakumar Sunitha, Hickman, Allison R, Sahu, Varun, Lee, Rachel, Xu, Xinjing, Lipieta, Natalie, Flashner, Samuel, Adeleke, Oluwatobi A, Popova, Irina K, Taylor, Hailey F, Noll, Kelsey, Windham, Carolina Lin, Maryanski, Danielle N, Venters, Bryan J, Nakagawa, Hiroshi, Keogh, Michael-Christopher, Armache, Karim-Jean, Lu, Chao
Format: Article
Language:English
Subjects:
Biomedicine and Life Sciences
Cancer
Cell Line, Tumor
CpG Islands
Cryoelectron Microscopy
DNA (Cytosine-5-)-Methyltransferases - genetics
DNA (Cytosine-5-)-Methyltransferases - metabolism
DNA Methylation
DNA Methyltransferase 3A
Histones - metabolism
Humans
Neoplasms - genetics
Neoplasms - metabolism
Neoplasms - pathology
Nucleosomes - metabolism
Polycomb-Group Proteins - genetics
Polycomb-Group Proteins - metabolism
Promoter Regions, Genetic
Protein Binding
SciAdv r-articles
Structural Biology
Ubiquitination
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Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adp0975