9E3R

Cryo-EM structure of PWWP domain deleted DNMT 3A2/3B3 in complex with a di-nucleosome

Summary for 9E3R

• Entry DOI: 10.2210/pdb9e3r/pdb
• Related: 9E00 9E05
• EMDB information: 47495
• Descriptor: Histone H3.2, S-ADENOSYL-L-HOMOCYSTEINE, Histone H4, ... (10 entities in total)
• Functional Keywords: dna methylation, dnmt 3a2/3b3, di-nucleosome, dna binding protein, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 26
• Total formula weight: 1076793.34

Authors

Xie, X.,Liu, M.,Zhou, X.E.,Worden, E.,Jones, P. (deposition date: 2024-10-23, release date: 2026-02-18, Last modification date: 2026-08-12)

Primary citation

Xie, X.,Liu, M.,Chua, G.N.L.,Zhou, X.E.,Dykstra, M.L.,Liu, S.,Jones, P.A.,Worden, E.J.
Nucleosome spacing regulates linker methylation by DNMT3A2/3B3.
Mol.Cell, 86:834-850.e9, 2026

PubMed Abstract: De novo CpG methylation (mCpG) is deposited by DNMT3A and DNMT3B, which target DNA linkers between nucleosomes. Cells contain millions of unique linkers, but the rules dictating which linkers get targeted by DNMT3 enzymes are not understood. We show that nucleosome spacing controls linker DNA methylation and H3K36me2 recognition by human DNMT3A2/3B3, linking de novo methylation to chromatin architecture. We present structures of DNMT3A2/3B3 bound to dinucleosomes, revealing that short linkers promote dinucleosome bridging, blocking access to linker DNA and suppressing methylation, whereas long linkers allow DNMT3A2/3B3 to engage each nucleosome separately and methylate linker DNA. Finally, we show that DNMT3A2/3B3 positions proline-tryptophan-tryptophan-proline (PWWP) domains to scan for H3K36me2. However, H3K36me2 recognition is blocked when DNMT3A2/3B3 bridges dinucleosomes with short linkers, imposing an additional structural constraint on DNMT3A2/3B3 function. Together, these findings uncover the mechanisms that govern de novo methylation in chromatin and explain how DNMT3 enzymes target linkers in cells.

PubMed: 41742418
DOI: 10.1016/j.molcel.2026.01.030

Experimental method

ELECTRON MICROSCOPY (6.9 Å)