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

作者：Kristjan H. Gretarsson, Stephen Abini-Agbomson, Susan L. Gloor, Daniel N. Weinberg, Jamie L McCuiston, Vishnu Udayakumar Sunita Kumary, Allison R. Hickman, Varun Sahu, Rachel Lee, Xinjing Xu, Natalie Lytell, Samuel P. Flashner, Oluwatobi A. Adeleke, Irina K Popova, Hailey F. Taylor, Kelsey E. Noll, Carolina Lin Windham, Danielle N Maryanski, Bryan J. Venters, Hiroshi Nakagawa, Michael‐Christopher Keogh, Karim‐Jean Armache, Chao Lü · 发表于：Science Advances · 年份：2024 · DOI：10.1126/sciadv.adp0975 · 被引用次数：26 · 研究领域：Epigenetics and DNA Methylation、RNA modifications and cancer、Genomics and Chromatin Dynamics

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.