biostudies-literatureChen XU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesU.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)NIEHS NIH HHSU.S. Department of Health & Human Services | NIH | National Cancer InstituteU.S. Department of Health & Human Services | NIH | National Institute of Environmental Health SciencesNCI NIH HHSNIGMS NIH HHS6217https://www.ebi.ac.uk/biostudies/studies/S-EPMC11266573biostudies-literatureUnknown15(1)Isoform 1 of DNA methyltransferase DNMT3A (DNMT3A1) specifically recognizes nucleosome monoubiquitylated at histone H2A lysine-119 (H2AK119ub1) for establishment of DNA methylation. Mis-regulation of this process may cause aberrant DNA methylation and pathogenesis. However, the molecular basis underlying DNMT3A1-nucleosome interaction remains elusive. Here we report the cryo-EM structure of DNMT3A1's ubiquitin-dependent recruitment (UDR) fragment complexed with H2AK119ub1-modified nucleosome. DNMT3A1 UDR occupies an extensive nucleosome surface, involving the H2A-H2B acidic patch, a surface groove formed by H2A and H3, nucleosomal DNA, and H2AK119ub1. The DNMT3A1 UDR's interaction with H2AK119ub1 affects the functionality of DNMT3A1 in cells in a context-dependent manner. Our structural anNature communicationsStructural basis for the H2AK119ub1-specific DNMT3A-nucleosome interaction.PMC11266573R01 GM129325R01 CA215284R35 ES031707U24 GM129539R35 GM119721R01 CA211336R35GM119721Fang JGuo YLu JChen XZhao TWang YWang GGSong JfalseStructural basis for the H2AK119ub1-specific DNMT3A-nucleosome interaction.Isoform 1 of DNA methyltransferase DNMT3A (DNMT3A1) specifically recognizes nucleosome monoubiquitylated at histone H2A lysine-119 (H2AK119ub1) for establishment of DNA methylation. Mis-regulation of this process may cause aberrant DNA methylation and pathogenesis. However, the molecular basis underlying DNMT3A1-nucleosome interaction remains elusive. Here we report the cryo-EM structure of DNMT3A1's ubiquitin-dependent recruitment (UDR) fragment complexed with H2AK119ub1-modified nucleosome. DNMT3A1 UDR occupies an extensive nucleosome surface, involving the H2A-H2B acidic patch, a surface groove formed by H2A and H3, nucleosomal DNA, and H2AK119ub1. The DNMT3A1 UDR's interaction with H2AK119ub1 affects the functionality of DNMT3A1 in cells in a context-dependent manner. Our structural an2024-01-01T00:00:00Z2024 Jul2026-06-02T05:04:31.578Z2025-04-19T13:10:59.176ZS-EPMC112665733904367810.1038/s41467-024-50526-3