A bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomes

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dc.contributor.authorFoglizzo M
dc.contributor.authorMiddleton AJ
dc.contributor.authorBurgess AE
dc.contributor.authorCrowther JM
dc.contributor.authorDobson RCJ
dc.contributor.authorMurphy JM
dc.contributor.authorDay CL
dc.contributor.authorMace PD
dc.date.accessioned2019-09-27T02:40:00Z
dc.date.available2019-09-27T02:40:00Z
dc.date.issued2018en
dc.date.updated2018-10-31T19:27:29Z
dc.description.abstractAttachment of ubiquitin to lysine 119 of Histone 2A (H2AK119Ub) is an epigenetic mark characteristic of repressed developmental genes, which is removed by the Polycomb Repressive-Deubiquitinase (PR-DUB) complex. Here we report the crystal structure of the Drosophila PR-DUB, revealing that the deubiquitinase Calypso and its activating partner ASX form a 2:2 complex. The bidentate Calypso–ASX complex is generated by dimerisation of two activated Calypso proteins through their coiled-coil regions. Disrupting the Calypso dimer interface does not affect inherent catalytic activity, but inhibits removal of H2AK119Ub as a consequence of impaired recruitment to nucleosomes. Mutating the equivalent surface on the human counterpart, BAP1, also compromises activity on nucleosomes. Together, this suggests that high local concentrations drive assembly of bidentate PR-DUB complexes on chromatin—providing a mechanistic basis for enhanced PR-DUB activity at specific genomic foci, and the impact of distinct classes of PR-DUB mutations in tumorigenesis.en
dc.identifier.doihttps://doi.org/10.1038/s41467-018-06186-1
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/10092/17318
dc.languageEnglish
dc.language.isoen
dc.rightsOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.en
dc.subject.anzsrcField of Research::03 - Chemical Sciences::0304 - Medicinal and Biomolecular Chemistryen
dc.titleA bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomesen
dc.typeJournal Articleen
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