dc.contributor.author | Bajrami, I | |
dc.contributor.author | Walker, C | |
dc.contributor.author | Krastev, DB | |
dc.contributor.author | Weekes, D | |
dc.contributor.author | Song, F | |
dc.contributor.author | Wicks, AJ | |
dc.contributor.author | Alexander, J | |
dc.contributor.author | Haider, S | |
dc.contributor.author | Brough, R | |
dc.contributor.author | Pettitt, SJ | |
dc.contributor.author | Tutt, ANJ | |
dc.contributor.author | Lord, CJ | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2021-11-19T09:16:04Z | |
dc.date.available | 2021-11-19T09:16:04Z | |
dc.date.issued | 2021-11-08 | |
dc.identifier | https://www.ncbi.nlm.nih.gov/pubmed/34750509 | |
dc.identifier | 10.1038/s42003-021-02770-2 | |
dc.identifier.citation | Commun Biol, 2021, 4 (1), pp. 1270 - ? | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4883 | |
dc.identifier.eissn | 2399-3642 | |
dc.identifier.doi | 10.1038/s42003-021-02770-2 | |
dc.description.abstract | PARP 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.extent | 1270 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PORTFOLIO | |
dc.title | Sirtuin inhibition is synthetic lethal with BRCA1 or BRCA2 deficiency. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-10-06 | |
rioxxterms.versionofrecord | 10.1038/s42003-021-02770-2 | |
rioxxterms.licenseref.startdate | 2021-11-08 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Commun Biol | |
pubs.issue | 1 | |
pubs.notes | Not 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-status | Published online | |
pubs.volume | 4 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Krastev, Dragomir | |
dc.contributor.icrauthor | Song, Feifei | |
dc.contributor.icrauthor | Wicks, Andrew | |
dc.contributor.icrauthor | Haider, Syed | |
dc.contributor.icrauthor | Pettitt, Stephen | |
dc.contributor.icrauthor | Tutt, Andrew | |
dc.contributor.icrauthor | Lord, Christopher | |