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

Kristjan H. Gretarsson; Stephen Abini-Agbomson; Susan L. Gloor; Daniel N. Weinberg; Jamie L McCuiston; Vishnu U. Sunitha Kumary; Allison R. Hickman; Varun Sahu; Rachel Lee; Xinjing Xu; Natalie Lipieta; Samuel P. Flashner; Oluwatobi A. Adeleke; Irina K Popova; Hailey F. Taylor; Kelsey E. Noll; Carolina P. Lin; Danielle N Maryanski; Bryan J. Venters; Hiroshi Nakagawa; Michael‐Christopher Keogh; Karim‐Jean Armache; Chao Lü

doi:10.1126/sciadv.adp0975

Cancer BiologyScience AdvancesAug 28, 2024

Peer-reviewed journal article

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

Kristjan H. Gretarsson iD, Stephen Abini-Agbomson iD, Susan L. Gloor iD, Daniel N. Weinberg iD, Jamie L McCuiston iD, Vishnu U. Sunitha Kumary iD, Allison R. Hickman iD, Varun Sahu iD, Rachel Lee iD, Xinjing Xu iD, Natalie Lipieta, Samuel P. Flashner iD, Oluwatobi A. Adeleke iD, Irina K Popova iD, Hailey F. Taylor iD, Kelsey E. Noll iD, Carolina P. Lin iD, Danielle N Maryanski iD, Bryan J. Venters iD, Hiroshi Nakagawa iD, Michael‐Christopher Keogh iD, Karim‐Jean Armache iD, Chao Lü iD

Abstract

During tumor development, promoter CpG islands (CGIs) that are normally silenced by Polycomb repressive complexes (PRCs) become DNA hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) catalyze CpG methylation at PRC-regulated regions remains unclear. Here we report a cryo-EM structure of the DNMT3A long isoform (DNMT3A1) N-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine 119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 N-terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Furthermore, aberrant redistribution of DNMT3A1 to Polycomb target genes inhibits their transcriptional activation during cell differentiation and recapitulates the cancer-associated DNA hypermethylation signature. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for countering promoter CGI DNA hypermethylation, a major molecular hallmark of cancer.

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