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dc.contributor.authorMalvezzi, Francesca
dc.contributor.authorStubbs, Christopher J
dc.contributor.authorJowitt, Thomas A
dc.contributor.authorDale, Ian L
dc.contributor.authorGuo, Xieyang
dc.contributor.authorDeGnore, Jon P
dc.contributor.authorDegliesposti, Gianluca
dc.contributor.authorSkehel, J Mark
dc.contributor.authorBannister, Andrew
dc.contributor.authorMcAlister, Mark S
dc.date.accessioned2021-11-09T16:34:39Z
dc.date.available2021-11-09T16:34:39Z
dc.date.issued2021-11-09
dc.date.submitted2020-07-16
dc.identifier.issn2399-3642
dc.identifier.others42003-021-02750-6
dc.identifier.other2750
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330502
dc.descriptionFunder: AstraZeneca; doi: https://doi.org/10.13039/100004325
dc.descriptionFunder: AstraZeneca postdoc fund
dc.description.abstractBromodomain-containing protein 4 (BRD4) is an epigenetic reader and oncology drug target that regulates gene transcription through binding to acetylated chromatin via bromodomains. Phosphorylation by casein kinase II (CK2) regulates BRD4 function, is necessary for active transcription and is involved in resistance to BRD4 drug inhibition in triple-negative breast cancer. Here, we provide the first biophysical analysis of BRD4 phospho-regulation. Using integrative structural biology, we show that phosphorylation by CK2 modulates the dimerization of human BRD4. We identify two conserved regions, a coiled-coil motif and the Basic-residue enriched Interaction Domain (BID), essential for the BRD4 structural rearrangement, which we term the phosphorylation-dependent dimerization domain (PDD). Finally, we demonstrate that bivalent inhibitors induce a conformational change within BRD4 dimers in vitro and in cancer cells. Our results enable the proposal of a model for BRD4 activation critical for the characterization of its protein-protein interaction network and for the development of more specific therapeutics.
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.subjectArticle
dc.subject/631/57
dc.subject/631/535
dc.subject/631/57/2272/2276
dc.subject/9
dc.subject/14/33
dc.subject/82/16
dc.subject/82/29
dc.subject/82/58
dc.subject/82/83
dc.subjectarticle
dc.titlePhosphorylation-dependent BRD4 dimerization and implications for therapeutic inhibition of BET family proteins.
dc.typeArticle
dc.date.updated2021-11-09T16:34:37Z
prism.issueIdentifier1
prism.publicationNameCommun Biol
prism.volume4
dc.identifier.doi10.17863/CAM.77945
dcterms.dateAccepted2021-09-27
rioxxterms.versionofrecord10.1038/s42003-021-02750-6
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidSkehel, J Mark [0000-0002-2432-0901]
dc.contributor.orcidBannister, Andrew [0000-0002-6312-4436]
dc.contributor.orcidMcAlister, Mark S [0000-0003-3986-1767]
dc.identifier.eissn2399-3642
pubs.funder-project-idCancer Research UK (C6946/A24843)
pubs.funder-project-idWellcome Trust (203144/Z/16/Z)
cam.issuedOnline2021-11-09


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