8UW1

Cryo-EM structure of DNMT3A1 UDR in complex with H2AK119Ub-nucleosome

8UW1 の概要

• エントリーDOI: 10.2210/pdb8uw1/pdb
• EMDBエントリー: 42636
• 分子名称: Histone H3.2, Histone H4, Histone H2A, ... (7 entities in total)
• 機能のキーワード: dnmt3a1, chromatin, h2a lysine 119 monoubiquitination, dna methyltransferase, gene regulation
• 由来する生物種: Xenopus laevis (African clawed frog); 詳細
• タンパク質・核酸の鎖数: 11
• 化学式量合計: 208966.33

構造登録者

Gretarsson, K.,Abini-Agbomson, S.,Armache, K.-J.,Lu, C. (登録日: 2023-11-05, 公開日: 2024-09-11, 最終更新日: 2025-05-21)

主引用文献

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

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: 39196936
DOI: 10.1126/sciadv.adp0975

実験手法

ELECTRON MICROSCOPY (2.88 Å)