View source for 8uw1


==Cryo-EM structure of DNMT3A1 UDR in complex with H2AK119Ub-nucleosome==
<StructureSection load='8uw1' size='340' side='right'caption='[[8uw1]], [[Resolution|resolution]] 2.88&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8uw1]] is a 11 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_'BL21-Gold(DE3)pLysS_AG' Escherichia coli 'BL21-Gold(DE3)pLysS AG'], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Xenopus_laevis Xenopus laevis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8UW1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8UW1 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.88&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8uw1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8uw1 OCA], [https://pdbe.org/8uw1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8uw1 RCSB], [https://www.ebi.ac.uk/pdbsum/8uw1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8uw1 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/H32_XENLA H32_XENLA] Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.
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== Publication Abstract from PubMed ==
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.

Cancer-associated DNA hypermethylation of Polycomb targets requires DNMT3A dual recognition of histone H2AK119 ubiquitination and the nucleosome acidic patch.,Gretarsson KH, Abini-Agbomson S, Gloor SL, Weinberg DN, McCuiston JL, Kumary VUS, Hickman AR, Sahu V, Lee R, Xu X, Lipieta N, Flashner S, Adeleke OA, Popova IK, Taylor HF, Noll K, Windham CL, Maryanski DN, Venters BJ, Nakagawa H, Keogh MC, Armache KJ, Lu C Sci Adv. 2024 Aug 30;10(35):eadp0975. doi: 10.1126/sciadv.adp0975. Epub 2024 Aug , 28. PMID:39196936<ref>PMID:39196936</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8uw1" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Xenopus laevis]]
[[Category: Abini-Agbomson S]]
[[Category: Armache K-J]]
[[Category: Gretarsson K]]
[[Category: Lu C]]