1. Structural basis for the H2AK119ub1-specific DNMT3A-nucleosome interaction.
- Author
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Chen, Xinyi, Guo, Yiran, Zhao, Ting, Lu, Jiuwei, Fang, Jian, Wang, Yinsheng, Wang, Gang, and Song, Jikui
- Subjects
Nucleosomes ,DNA Methyltransferase 3A ,DNA (Cytosine-5-)-Methyltransferases ,Histones ,Humans ,DNA Methylation ,Protein Binding ,Cryoelectron Microscopy ,Animals ,Mice ,Ubiquitination ,Polycomb Repressive Complex 2 ,HEK293 Cells ,Models ,Molecular - 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 DNMT3A1s 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 UDRs 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.
- Published
- 2024