Publication:
Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality.

cris.virtual.author-orcid0000-0003-2044-9844
cris.virtualsource.author-orcid3ce5c712-81bb-4245-9893-0aa479809c45
datacite.rightsopen.access
dc.contributor.authorGogola, Ewa
dc.contributor.authorDuarte, Alexandra A
dc.contributor.authorde Ruiter, Julian R
dc.contributor.authorWiegant, Wouter W
dc.contributor.authorSchmid, Jonas A
dc.contributor.authorde Bruijn, Roebi
dc.contributor.authorJames, Dominic I
dc.contributor.authorGuerrero Llobet, Sergi
dc.contributor.authorVis, Daniel J
dc.contributor.authorAnnunziato, Stefano
dc.contributor.authorvan den Broek, Bram
dc.contributor.authorBarazas, Marco
dc.contributor.authorKersbergen, Ariena
dc.contributor.authorvan de Ven, Marieke
dc.contributor.authorTarsounas, Madalena
dc.contributor.authorOgilvie, Donald J
dc.contributor.authorvan Vugt, Marcel
dc.contributor.authorWessels, Lodewyk F A
dc.contributor.authorBartkova, Jirina
dc.contributor.authorGromova, Irina
dc.contributor.authorAndújar-Sánchez, Miguel
dc.contributor.authorBartek, Jiri
dc.contributor.authorLopes, Massimo
dc.contributor.authorvan Attikum, Haico
dc.contributor.authorBorst, Piet
dc.contributor.authorJonkers, Jos
dc.contributor.authorRottenberg, Sven
dc.date.accessioned2025-01-08T20:33:35Z
dc.date.available2025-01-08T20:33:35Z
dc.date.issued2018-06-11
dc.description.abstractInhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically.
dc.description.numberOfPages16
dc.description.sponsorshipInstitut für Tierpathologie (ITPA)
dc.identifier.doi10.7892/boris.122087
dc.identifier.pmid29894693
dc.identifier.publisherDOI10.1016/j.ccell.2018.05.008
dc.identifier.urihttps://boris-portal.unibe.ch/handle/20.500.12422/200300
dc.language.isoen
dc.publisherCell Press
dc.relation.ispartofCancer cell
dc.relation.issn1535-6108
dc.relation.organizationDCD5A442C208E17DE0405C82790C4DE2
dc.relation.organizationDCD5A442C072E17DE0405C82790C4DE2
dc.relation.organizationDCD5A442C1CCE17DE0405C82790C4DE2
dc.subjectBRCA1 BRCA2 PARG PARP inhibitor PARP1 PARylation drug resistance homologous recombination replication fork
dc.subject.ddc500 - Science::570 - Life sciences; biology
dc.subject.ddc600 - Technology::610 - Medicine & health
dc.subject.ddc600 - Technology::630 - Agriculture
dc.titleSelective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality.
dc.typearticle
dspace.entity.typePublication
dspace.file.typetext
dspace.file.typetext
oaire.citation.endPage1093.e12
oaire.citation.issue6
oaire.citation.startPage1078
oaire.citation.volume33
oairecerif.author.affiliationInstitut für Tierpathologie (ITPA)
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unibe.date.embargoChanged2019-07-01 00:33:04
unibe.date.licenseChanged2019-10-24 08:36:12
unibe.description.ispublishedpub
unibe.eprints.legacyId122087
unibe.journal.abbrevTitleCANCER CELL
unibe.refereedtrue
unibe.subtype.articlejournal

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