Department of Biochemistry, University of California, Riverside, CA, 92521, USA.
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
Nat Commun. 2024 Jul 23;15(1):6217. doi: 10.1038/s41467-024-50526-3.
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.
DNA 甲基转移酶 DNMT3A（DNMT3A1）的同工型 1 特异性识别组蛋白 H2A 赖氨酸 119（H2AK119ub1）单泛素化的核小体，用于建立 DNA 甲基化。该过程的失调可能导致异常的 DNA 甲基化和发病机制。然而，DNMT3A1-核小体相互作用的分子基础仍然难以捉摸。在这里，我们报告了 DNMT3A1 的泛素依赖性募集（UDR）片段与 H2AK119ub1 修饰核小体复合物的冷冻电镜结构。DNMT3A1 UDR 占据了广泛的核小体表面，涉及 H2A-H2B 酸性斑点、由 H2A 和 H3 形成的表面凹槽、核小体 DNA 和 H2AK119ub1。DNMT3A1 UDR 与 H2AK119ub1 的相互作用以依赖于上下文的方式影响细胞中 DNMT3A1 的功能。我们的结构和生化分析还揭示了 DNMT3A1 和 JARID2（多梳抑制复合物 2（PRC2）的共因子）之间竞争核小体结合的竞争，这表明不同的表观遗传途径之间存在相互作用。总之，这项研究报告了 H2AK119ub1 依赖性 DNMT3A1-核小体结合的分子基础，对 DNMT3A1 介导的发育过程中的 DNA 甲基化具有重要意义。
