9MP0

The cryo-EM structure of the human DNA methyltransferases DNMT3A2 and DNMT3L dodecamer

Summary for 9MP0

• Entry DOI: 10.2210/pdb9mp0/pdb
• EMDB information: 48496
• Descriptor: DNA (cytosine-5)-methyltransferase 3A, DNA (cytosine-5)-methyltransferase 3-like, ZINC ION, ... (4 entities in total)
• Functional Keywords: methyltransferase, dodecamer, transferase, transferase-dna complex, dna binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 10
• Total formula weight: 715416.54

Authors

Yan, Y.,Zhou, X.E.,Xu, T.H. (deposition date: 2024-12-29, release date: 2025-10-08, Last modification date: 2025-11-19)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.66 Å)