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dc.contributor.authorBajrami, I
dc.contributor.authorWalker, C
dc.contributor.authorKrastev, DB
dc.contributor.authorWeekes, D
dc.contributor.authorSong, F
dc.contributor.authorWicks, AJ
dc.contributor.authorAlexander, J
dc.contributor.authorHaider, S
dc.contributor.authorBrough, R
dc.contributor.authorPettitt, SJ
dc.contributor.authorTutt, ANJ
dc.contributor.authorLord, CJ
dc.coverage.spatialEngland
dc.date.accessioned2021-11-19T09:16:04Z
dc.date.available2021-11-19T09:16:04Z
dc.date.issued2021-11-08
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/34750509
dc.identifier10.1038/s42003-021-02770-2
dc.identifier.citationCommun Biol, 2021, 4 (1), pp. 1270 - ?
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4883
dc.identifier.eissn2399-3642
dc.identifier.doi10.1038/s42003-021-02770-2
dc.description.abstractPARP enzymes utilise NAD+ as a co-substrate for their enzymatic activity. Inhibition of PARP1 is synthetic lethal with defects in either BRCA1 or BRCA2. In order to assess whether other genes implicated in NAD+ metabolism were synthetic lethal with BRCA1 or BRCA2 gene defects, we carried out a genetic screen, which identified a synthetic lethality between BRCA1 and genetic inhibition of either of two sirtuin (SIRT) enzymes, SIRT1 or SIRT6. This synthetic lethal interaction was replicated using small-molecule SIRT inhibitors and was associated with replication stress and increased cellular PARylation, in contrast to the decreased PARylation associated with BRCA-gene/PARP inhibitor synthetic lethality. SIRT/BRCA1 synthetic lethality was reversed by genetic ablation of either PARP1 or the histone PARylation factor-coding gene HPF1, implicating PARP1/HPF1-mediated serine ADP-ribosylation as part of the mechanistic basis of this synthetic lethal effect. These observations suggest that PARP1/HPF1-mediated serine ADP-ribosylation, when driven by SIRT inhibition, can inadvertently inhibit the growth of BRCA-gene mutant cells.
dc.format.extent1270 - ?
dc.languageeng
dc.language.isoeng
dc.publisherNATURE PORTFOLIO
dc.titleSirtuin inhibition is synthetic lethal with BRCA1 or BRCA2 deficiency.
dc.typeJournal Article
dcterms.dateAccepted2021-10-06
rioxxterms.versionofrecord10.1038/s42003-021-02770-2
rioxxterms.licenseref.startdate2021-11-08
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCommun Biol
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/20/21 Starting Cohort
pubs.publication-statusPublished online
pubs.volume4
pubs.embargo.termsNot known
icr.researchteamGene Function
dc.contributor.icrauthorKrastev, Dragomir
dc.contributor.icrauthorSong, Feifei
dc.contributor.icrauthorWicks, Andrew
dc.contributor.icrauthorHaider, Syed
dc.contributor.icrauthorPettitt, Stephen
dc.contributor.icrauthorTutt, Andrew
dc.contributor.icrauthorLord, Christopher


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