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dc.contributor.authorZimmermann, M
dc.contributor.authorMurina, O
dc.contributor.authorReijns, MAM
dc.contributor.authorAgathanggelou, A
dc.contributor.authorChallis, R
dc.contributor.authorTarnauskaitė, Ž
dc.contributor.authorMuir, M
dc.contributor.authorFluteau, A
dc.contributor.authorAregger, M
dc.contributor.authorMcEwan, A
dc.contributor.authorYuan, W
dc.contributor.authorClarke, M
dc.contributor.authorLambros, MB
dc.contributor.authorPaneesha, S
dc.contributor.authorMoss, P
dc.contributor.authorChandrashekhar, M
dc.contributor.authorAngers, S
dc.contributor.authorMoffat, J
dc.contributor.authorBrunton, VG
dc.contributor.authorHart, T
dc.contributor.authorde Bono, J
dc.contributor.authorStankovic, T
dc.contributor.authorJackson, AP
dc.contributor.authorDurocher, D
dc.date.accessioned2019-09-16T15:17:10Z
dc.date.issued2018-07-04
dc.identifier.citationNature, 2018, 559 (7713), pp. 285 - 289
dc.identifier.issn0028-0836
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3335
dc.identifier.eissn1476-4687
dc.identifier.doi10.1038/s41586-018-0291-z
dc.description.abstractThe observation that BRCA1- and BRCA2-deficient cells are sensitive to inhibitors of poly(ADP-ribose) polymerase (PARP) has spurred the development of cancer therapies that use these inhibitors to target deficiencies in homologous recombination1. The cytotoxicity of PARP inhibitors depends on PARP trapping, the formation of non-covalent protein-DNA adducts composed of inhibited PARP1 bound to DNA lesions of unclear origins1-4. To address the nature of such lesions and the cellular consequences of PARP trapping, we undertook three CRISPR (clustered regularly interspersed palindromic repeats) screens to identify genes and pathways that mediate cellular resistance to olaparib, a clinically approved PARP inhibitor1. Here we present a high-confidence set of 73 genes, which when mutated cause increased sensitivity to PARP inhibitors. In addition to an expected enrichment for genes related to homologous recombination, we discovered that mutations in all three genes encoding ribonuclease H2 sensitized cells to PARP inhibition. We establish that the underlying cause of the PARP-inhibitor hypersensitivity of cells deficient in ribonuclease H2 is impaired ribonucleotide excision repair5. Embedded ribonucleotides, which are abundant in the genome of cells deficient in ribonucleotide excision repair, are substrates for cleavage by topoisomerase 1, resulting in PARP-trapping lesions that impede DNA replication and endanger genome integrity. We conclude that genomic ribonucleotides are a hitherto unappreciated source of PARP-trapping DNA lesions, and that the frequent deletion of RNASEH2B in metastatic prostate cancer and chronic lymphocytic leukaemia could provide an opportunity to exploit these findings therapeutically.
dc.formatPrint-Electronic
dc.format.extent285 - 289
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectCell Line
dc.subjectHela Cells
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectNeoplasms
dc.subjectProstatic Neoplasms
dc.subjectDNA Damage
dc.subjectPiperazines
dc.subjectPhthalazines
dc.subjectDNA Topoisomerases, Type I
dc.subjectBRCA1 Protein
dc.subjectRibonucleotides
dc.subjectXenograft Model Antitumor Assays
dc.subjectDNA Repair
dc.subjectDNA Replication
dc.subjectGenes, BRCA1
dc.subjectGenome
dc.subjectFemale
dc.subjectMale
dc.subjectLeukemia, Lymphocytic, Chronic, B-Cell
dc.subjectRibonuclease H
dc.subjectCRISPR-Cas Systems
dc.subjectPoly(ADP-ribose) Polymerase Inhibitors
dc.subjectPoly (ADP-Ribose) Polymerase-1
dc.subjectGene Editing
dc.subjectSynthetic Lethal Mutations
dc.titleCRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions.
dc.typeJournal Article
dcterms.dateAccepted2018-06-07
rioxxterms.versionofrecord10.1038/s41586-018-0291-z
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-07-04
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature
pubs.issue7713
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.publication-statusPublished
pubs.volume559
pubs.embargo.termsNot known
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
dc.contributor.icrauthorDe Bono, Johannen


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