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dc.contributor.authorBusacca, Sara
dc.contributor.authorZhang, Qi
dc.contributor.authorSharkey, Annabel
dc.contributor.authorDawson, Alan G.
dc.contributor.authorMoore, David A.
dc.contributor.authorWaller, David A.
dc.contributor.authorNakas, Apostolos
dc.contributor.authorJones, Carolyn
dc.contributor.authorCain, Kelvin
dc.contributor.authorLuo, Jin-li
dc.contributor.authorSalcedo, Adriana
dc.contributor.authorSalaroglio, Iris Chiara
dc.contributor.authorRiganti, Chiara
dc.contributor.authorLe Quesne, John
dc.contributor.authorJohn, Tom
dc.contributor.authorBoutros, Paul C.
dc.contributor.authorZhang, Shu-Dong
dc.contributor.authorFennell, Dean A.
dc.date.accessioned2021-04-01T15:13:49Z
dc.date.available2021-04-01T15:13:49Z
dc.date.issued2021-04-01
dc.date.submitted2020-09-21
dc.identifier.others41598-021-86834-7
dc.identifier.other86834
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/319436
dc.description.abstractAbstract: We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.
dc.languageen
dc.publisherNature Publishing Group UK
dc.subjectArticle
dc.subject/631/67/1641
dc.subject/631/67
dc.subject/631/67/1059/602
dc.subject/631/80
dc.subject/631/80/83
dc.subjectarticle
dc.titleTranscriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression
dc.typeArticle
dc.date.updated2021-04-01T15:13:49Z
prism.issueIdentifier1
prism.publicationNameScientific Reports
prism.volume11
dc.identifier.doi10.17863/CAM.66558
dcterms.dateAccepted2021-01-18
rioxxterms.versionofrecord10.1038/s41598-021-86834-7
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.identifier.eissn2045-2322
pubs.funder-project-idThe British Lung Foundation (MESOUK15-11, MESOUK15-11)


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