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dc.contributor.authorPettitt, SJ
dc.contributor.authorKrastev, DB
dc.contributor.authorBrandsma, I
dc.contributor.authorDréan, A
dc.contributor.authorSong, F
dc.contributor.authorAleksandrov, R
dc.contributor.authorHarrell, MI
dc.contributor.authorMenon, M
dc.contributor.authorBrough, R
dc.contributor.authorCampbell, J
dc.contributor.authorFrankum, J
dc.contributor.authorRanes, M
dc.contributor.authorPemberton, HN
dc.contributor.authorRafiq, R
dc.contributor.authorFenwick, K
dc.contributor.authorSwain, A
dc.contributor.authorGuettler, S
dc.contributor.authorLee, J-M
dc.contributor.authorSwisher, EM
dc.contributor.authorStoynov, S
dc.contributor.authorYusa, K
dc.contributor.authorAshworth, A
dc.contributor.authorLord, CJ
dc.date.accessioned2018-05-23T11:19:44Z
dc.date.issued2018-05-10
dc.identifier.citationNature communications, 2018, 9 (1), pp. 1849 - ?
dc.identifier.issn2041-1723
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1686
dc.identifier.eissn2041-1723
dc.identifier.doi10.1038/s41467-018-03917-2
dc.description.abstractAlthough PARP inhibitors (PARPi) target homologous recombination defective tumours, drug resistance frequently emerges, often via poorly understood mechanisms. Here, using genome-wide and high-density CRISPR-Cas9 "tag-mutate-enrich" mutagenesis screens, we identify close to full-length mutant forms of PARP1 that cause in vitro and in vivo PARPi resistance. Mutations both within and outside of the PARP1 DNA-binding zinc-finger domains cause PARPi resistance and alter PARP1 trapping, as does a PARP1 mutation found in a clinical case of PARPi resistance. This reinforces the importance of trapped PARP1 as a cytotoxic DNA lesion and suggests that PARP1 intramolecular interactions might influence PARPi-mediated cytotoxicity. PARP1 mutations are also tolerated in cells with a pathogenic BRCA1 mutation where they result in distinct sensitivities to chemotherapeutic drugs compared to other mechanisms of PARPi resistance (BRCA1 reversion, 53BP1, REV7 (MAD2L2) mutation), suggesting that the underlying mechanism of PARPi resistance that emerges could influence the success of subsequent therapies.
dc.formatElectronic
dc.format.extent1849 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectMice, Inbred BALB C
dc.subjectHumans
dc.subjectMice
dc.subjectMice, Nude
dc.subjectNeoplasms
dc.subjectPhthalazines
dc.subjectBRCA1 Protein
dc.subjectXenograft Model Antitumor Assays
dc.subjectDNA Mutational Analysis
dc.subjectMutagenesis
dc.subjectZinc Fingers
dc.subjectDrug Resistance, Neoplasm
dc.subjectPoint Mutation
dc.subjectAged
dc.subjectFemale
dc.subjectCRISPR-Cas Systems
dc.subjectPoly(ADP-ribose) Polymerase Inhibitors
dc.subjectPrecision Medicine
dc.subjectMouse Embryonic Stem Cells
dc.subjectPoly (ADP-Ribose) Polymerase-1
dc.subjectWhole Genome Sequencing
dc.titleGenome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance.
dc.typeJournal Article
dcterms.dateAccepted2018-03-22
rioxxterms.versionofrecord10.1038/s41467-018-03917-2
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-05-10
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature communications
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/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Development & Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Development & Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Biology of Cell Signalling
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/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Development & Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Development & Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Biology of Cell Signalling
pubs.publication-statusPublished
pubs.volume9
pubs.embargo.termsNot known
icr.researchteamDevelopment & Canceren_US
icr.researchteamGene Functionen_US
icr.researchteamStructural Biology of Cell Signallingen_US
dc.contributor.icrauthorSong, Feifeien
dc.contributor.icrauthorLord, Christopheren
dc.contributor.icrauthorGuettler, Sebastianen
dc.contributor.icrauthorPettitt, Stephenen
dc.contributor.icrauthorCampbell, Jamesen
dc.contributor.icrauthorSwain, Amandaen
dc.contributor.icrauthorKrastev, Dragomiren


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