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| Title | Structural basis for the H2AK119ub1-specific DNMT3A-nucleosome interaction. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 6217, Year 2024 |
| Publish date | Jul 23, 2024 |
Authors | Xinyi Chen / Yiran Guo / Ting Zhao / Jiuwei Lu / Jian Fang / Yinsheng Wang / Gang Greg Wang / Jikui Song / ![]() |
| 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 ...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 links | Nat Commun / PubMed:39043678 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.23 - 5.4 Å |
| Structure data | ![]() EMDB-41920: Cryo-EM structure of human DNMT3A UDR bound to H2AK119ub1-modified nucleosome ![]() EMDB-41921: Cryo-EM structure of human DNMT3A UDR bound to H2AK119ub1-modified nucleosome EMDB-41922, PDB-8u5h: |
| Source |
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Keywords | STRUCTURAL PROTEIN/TRANSFERASE/DNA / DNA cytosine methyltransferase / STRUCTURAL PROTEIN-TRANSFERASE-DNA complex |
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