8U5H

Cryo-EM structure of human DNMT3A UDR bound to H2AK119ub1-modified nucleosome

Summary for 8U5H

• Entry DOI: 10.2210/pdb8u5h/pdb
• EMDB information: 41922
• Descriptor: DNA (cytosine-5)-methyltransferase 3A, nucleosome DNA, Ubiquitin, ... (8 entities in total)
• Functional Keywords: dna cytosine methyltransferase, structural protein-transferase-dna complex, structural protein/transferase/dna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 13
• Total formula weight: 251168.13

Authors

Chen, X.,Song, J. (deposition date: 2023-09-12, release date: 2024-06-12, Last modification date: 2025-05-21)

Primary citation

Chen, X.,Guo, Y.,Zhao, T.,Lu, J.,Fang, J.,Wang, Y.,Wang, G.G.,Song, J.
Structural basis for the H2AK119ub1-specific DNMT3A-nucleosome interaction.
Nat Commun, 15:6217-6217, 2024

PubMed Abstract: 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 and biochemical analysis also reveals competition between DNMT3A1 and JARID2, a cofactor of polycomb repression complex 2 (PRC2), for nucleosome binding, suggesting the interplay between different epigenetic pathways. Together, this study reports a molecular basis for H2AK119ub1-dependent DNMT3A1-nucleosome association, with important implications in DNMT3A1-mediated DNA methylation in development.

PubMed: 39043678
DOI: 10.1038/s41467-024-50526-3

Experimental method

ELECTRON MICROSCOPY (3.23 Å)