9MPP

The cryo-EM structure of nucleosome-bound DNA methyltransferases DNMT3A2 and DNMT3L

9MPP の概要

• エントリーDOI: 10.2210/pdb9mpp/pdb
• 関連するPDBエントリー: 9MP0 9MPO
• EMDBエントリー: 48494 48495 48496 48497 48498
• 分子名称: Histone H3.2, S-ADENOSYL-L-HOMOCYSTEINE, Histone H4, ... (10 entities in total)
• 機能のキーワード: methyltransferase, dnmt-nucleosome complex, transferase, transferase-dna complex, dna binding protein
• 由来する生物種: Xenopus laevis (African clawed frog); 詳細
• タンパク質・核酸の鎖数: 14
• 化学式量合計: 455838.66

構造登録者

Yan, Y.,Zhou, X.E.,Xu, T.H. (登録日: 2024-12-31, 公開日: 2025-10-08, 最終更新日: 2025-11-19)

主引用文献

Yan, Y.,Zhou, X.E.,Thomas, S.L.,Liu, M.,Lai, G.Q.,Worden, E.J.,Jones, P.A.,Xu, T.H.
Mechanisms of DNMT3A-3L-mediated de novo DNA methylation on chromatin.
Nat.Struct.Mol.Biol., 2025

PubMed Abstract: De novo DNA methylation is mediated by DNA methyltransferases DNMT3A and DNMT3B, in cooperation with the catalytically inactive paralogs DNMT3L and DNMT3B3. DNMT3L is predominantly expressed in embryonic stem cells to establish methylation patterns and is silenced upon differentiation, with DNMT3B3 substituting in somatic cells. Here we present high-resolution cryo-electron microscopy structures of nucleosome-bound, full-length DNMT3A2-3L and its oligomeric assemblies in the nucleosome-free state. We identified the critical role of DNMT3L as a histone modification sensor, guiding chromatin engagement through a mechanism distinct from DNMT3B3. The structures show a 180° rotated 'switching helix' in DNMT3L that prevents direct interaction with the nucleosome acidic patch. Instead, nucleosome binding is mediated by the DNMT3L ADD domain, while the DNMT3A PWWP domain exhibits reduced engagement in the absence of H3K36 methylation. The oligomeric arrangement of DNMT3A2-3L in nucleosome-free states highlights its dynamic assembly and potential allosteric regulation. We further capture dynamic structural movements of DNMT3A2-3L on nucleosomes. These findings uncover a previously unknown mechanism by which DNMT3A-3L mediates de novo DNA methylation on chromatin through complex assembly, histone tail sensing, dynamic DNA search and regulated nucleosome engagement, providing insights into epigenetic regulation.

PubMed: 41174279
DOI: 10.1038/s41594-025-01704-4

実験手法

ELECTRON MICROSCOPY (3.1 Å)