8UW1
Cryo-EM structure of DNMT3A1 UDR in complex with H2AK119Ub-nucleosome
Summary for 8UW1
| Entry DOI | 10.2210/pdb8uw1/pdb |
| EMDB information | 42636 |
| Descriptor | Histone H3.2, Histone H4, Histone H2A, ... (7 entities in total) |
| Functional Keywords | dnmt3a1, chromatin, h2a lysine 119 monoubiquitination, dna methyltransferase, gene regulation |
| Biological source | Xenopus laevis (African clawed frog) More |
| Total number of polymer chains | 11 |
| Total formula weight | 208966.33 |
| Authors | Gretarsson, K.,Abini-Agbomson, S.,Armache, K.-J.,Lu, C. (deposition date: 2023-11-05, release date: 2024-09-11, Last modification date: 2025-05-21) |
| Primary citation | Gretarsson, K.H.,Abini-Agbomson, S.,Gloor, S.L.,Weinberg, D.N.,McCuiston, J.L.,Kumary, V.U.S.,Hickman, A.R.,Sahu, V.,Lee, R.,Xu, X.,Lipieta, N.,Flashner, S.,Adeleke, O.A.,Popova, I.K.,Taylor, H.F.,Noll, K.,Windham, C.L.,Maryanski, D.N.,Venters, B.J.,Nakagawa, H.,Keogh, M.C.,Armache, K.J.,Lu, C. Cancer-associated DNA hypermethylation of Polycomb targets requires DNMT3A dual recognition of histone H2AK119 ubiquitination and the nucleosome acidic patch. Sci Adv, 10:eadp0975-eadp0975, 2024 Cited by PubMed Abstract: During tumor development, promoter CpG islands that are normally silenced by Polycomb repressive complexes (PRCs) become DNA-hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) [DNMT(s)] catalyze CpG methylation at PRC-regulated regions remains unclear. Here, we report a cryo-electron microscopy structure of the DNMT3A long isoform (DNMT3A1) amino-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine-119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 amino terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Further, aberrant redistribution of DNMT3A1 to Polycomb target genes recapitulates the cancer-associated DNA hypermethylation signature and inhibits their transcriptional activation during cell differentiation. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for mediating promoter CpG island DNA hypermethylation, a major molecular hallmark of cancer. PubMed: 39196936DOI: 10.1126/sciadv.adp0975 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.88 Å) |
Structure validation
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