8QZM

Structure of DNMT3A1 UDR region bound to H2AK119ub nucleosome

Summary for 8QZM

• Entry DOI: 10.2210/pdb8qzm/pdb
• EMDB information: 18778
• Descriptor: Histone H3 (Fragment), Histone H4, Histone H2A type 1, ... (7 entities in total)
• Functional Keywords: chromatin, nucleosome, methyltransferase, ubiquitin, dna binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 11
• Total formula weight: 331266.14

Authors

Burdett, H.,Wapenaar, H.,Wilson, M.D. (deposition date: 2023-10-27, release date: 2024-10-23, Last modification date: 2024-12-18)

Primary citation

Wapenaar, H.,Clifford, G.,Rolls, W.,Pasquier, M.,Burdett, H.,Zhang, Y.,Deak, G.,Zou, J.,Spanos, C.,Taylor, M.R.D.,Mills, J.,Watson, J.A.,Kumar, D.,Clark, R.,Das, A.,Valsakumar, D.,Bramham, J.,Voigt, P.,Sproul, D.,Wilson, M.D.
The N-terminal region of DNMT3A engages the nucleosome surface to aid chromatin recruitment.
Embo Rep., 25:5743-5779, 2024

PubMed Abstract: DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns in vertebrates. Here we structurally and biochemically explore the interaction of DNMT3A1 with diverse modified nucleosomes indicative of different chromatin environments. A cryo-EM structure of the full-length DNMT3A1-DNMT3L complex with a H2AK119ub nucleosome reveals that the DNMT3A1 ubiquitin-dependent recruitment (UDR) motif interacts specifically with H2AK119ub and makes extensive contacts with the core nucleosome histone surface. This interaction facilitates robust DNMT3A1 binding to nucleosomes, and previously unexplained DNMT3A disease-associated mutations disrupt this interface. Furthermore, the UDR-nucleosome interaction synergises with other DNMT3A chromatin reading elements in the absence of histone ubiquitylation. H2AK119ub does not stimulate DNMT3A DNA methylation activity, as observed for the previously described H3K36me2 mark, which may explain low levels of DNA methylation on H2AK119ub marked facultative heterochromatin. This study highlights the importance of multivalent binding of DNMT3A to histone modifications and the nucleosome surface and increases our understanding of how DNMT3A1 chromatin recruitment occurs.

PubMed: 39528729
DOI: 10.1038/s44319-024-00306-3

Experimental method

ELECTRON MICROSCOPY (3.1 Å)