Author:
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
Abstract
AbstractDuring tumor development, promoter CpG islands (CGIs) that are normally silenced by Polycomb repressive complexes (PRCs) become DNA hypermethylated. The molecular mechanism by whichde novoDNA 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.
Publisher
Cold Spring Harbor Laboratory