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TitleStructural basis for the H2AK119ub1-specific DNMT3A-nucleosome interaction.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 6217, Year 2024
Publish dateJul 23, 2024
AuthorsXinyi Chen / Yiran Guo / Ting Zhao / Jiuwei Lu / Jian Fang / Yinsheng Wang / Gang Greg Wang / Jikui Song /
PubMed AbstractIsoform 1 of DNA methyltransferase DNMT3A (DNMT3A1) specifically recognizes nucleosome monoubiquitylated at histone H2A lysine-119 (H2AK119ub1) for establishment of DNA methylation. Mis-regulation of ...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.
External linksNat Commun / PubMed:39043678 / PubMed Central
MethodsEM (single particle)
Resolution3.23 - 5.4 Å
Structure data

EMDB-41920: Cryo-EM structure of human DNMT3A UDR bound to H2AK119ub1-modified nucleosome
Method: EM (single particle) / Resolution: 3.26 Å

EMDB-41921: Cryo-EM structure of human DNMT3A UDR bound to H2AK119ub1-modified nucleosome
Method: EM (single particle) / Resolution: 5.4 Å

EMDB-41922, PDB-8u5h:
Cryo-EM structure of human DNMT3A UDR bound to H2AK119ub1-modified nucleosome
Method: EM (single particle) / Resolution: 3.23 Å

Source
  • homo sapiens (human)
  • xenopus laevis (African clawed frog)
KeywordsSTRUCTURAL PROTEIN/TRANSFERASE/DNA / DNA cytosine methyltransferase / STRUCTURAL PROTEIN-TRANSFERASE-DNA complex

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