Year: 2025
Type: conference-abstract
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.This research was supported by NIH grants (R35 GM119721 to J.S., R01 CA215284 and R01 CA211336 to G.G.W., and R35 ES031707
Source: Journal of Biological Chemistry
Author: Nada Jabado
Institution: McGill University
Language: Spanish
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,430
OpenAlex ID: W4411258340