2019
Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51
Kaplan AR, Gueble SE, Liu Y, Oeck S, Kim H, Yun Z, Glazer PM. Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51. Science Translational Medicine 2019, 11 PMID: 31092693, PMCID: PMC6626544, DOI: 10.1126/scitranslmed.aav4508.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBRCA1 ProteinBRCA2 ProteinCell Line, TumorDNA RepairDown-RegulationE2F4 Transcription FactorFemaleGene Expression Regulation, NeoplasticHumansMice, NudePoly(ADP-ribose) Polymerase InhibitorsQuinazolinesRad51 RecombinaseReceptors, Platelet-Derived Growth FactorTumor HypoxiaVascular Endothelial Growth Factor Receptor-2Xenograft Model Antitumor AssaysConceptsHomology-directed DNA repairDNA repairE2F transcription factor 4Protein phosphatase 2ATranscription factor 4DNA repair inhibitorsPhosphatase 2ARAD51 recombinaseTranscriptional corepressorMouse tumor xenograftsSynthetic lethalityGene expressionRB2/Mouse bone marrowGrowth factor receptor inhibitionRepair inhibitorsUnknown mechanismPlatelet-derived growth factor receptor inhibitionFactor 4Human tumorsInhibitor olaparibPARP inhibitorsMutationsCombination of cediranibCancer therapy
2018
PTEN Regulates Non-Homologous End Joining by Epigenetic Induction of NHEJ1/XLF
Sulkowski PL, Scanlon SE, Oeck S, Glazer PM. PTEN Regulates Non-Homologous End Joining by Epigenetic Induction of NHEJ1/XLF. Molecular Cancer Research 2018, 16: molcanres.0581.2017. PMID: 29739874, PMCID: PMC6072556, DOI: 10.1158/1541-7786.mcr-17-0581.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksKey DNA repair pathwaysCytotoxic DNA lesionsXRCC4-like factorPatient-derived melanomasDNA repair pathwaysDouble-strand breaksNovel regulatory roleTumor suppressor geneSuppression of PTENHistone acetyltransferasesDSB repairGenomic analysisNHEJ defectsNonhomologous endRepair pathwaysGene promoterNovel functionRegulatory acetylationNHEJ deficiencyDNA lesionsRegulatory roleSuppressor geneNHEJ DSB repairNHEJ
2017
2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity
Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H, Liu Y, Sundaram RK, Hegan DC, Fons NR, Breuer GA, Song Y, Mishra-Gorur K, De Feyter HM, de Graaf RA, Surovtseva YV, Kachman M, Halene S, Günel M, Glazer PM, Bindra RS. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Science Translational Medicine 2017, 9 PMID: 28148839, PMCID: PMC5435119, DOI: 10.1126/scitranslmed.aal2463.Peer-Reviewed Original ResearchConceptsIsocitrate dehydrogenase 1PARP inhibitor sensitivityPossible therapeutic strategiesHomologous recombination defectsTherapeutic strategiesTumor xenograftsInhibitor sensitivityPathologic processesSmall molecule inhibitorsIDH1/2 mutationsTumor progressionIDH2 mutationsMutant IDHPolymerase inhibitorsGlioma cellsTumor cellsHR deficiencyPARP inhibitionIDH mutationsInhibitory effectDehydrogenase 1Neomorphic activityMutant IDH1 enzymeDependent dioxygenasesMutant cells
2013
Oxidative Stress in Mammalian Cells Impinges on the Cysteines Redox State of Human XRCC3 Protein and on Its Cellular Localization
Girard P, Graindorge D, Smirnova V, Rigolet P, Francesconi S, Scanlon S, Sage E. Oxidative Stress in Mammalian Cells Impinges on the Cysteines Redox State of Human XRCC3 Protein and on Its Cellular Localization. PLOS ONE 2013, 8: e75751. PMID: 24116071, PMCID: PMC3793007, DOI: 10.1371/journal.pone.0075751.Peer-Reviewed Original ResearchConceptsHomologous recombinationSensitivity to camptothecinCysteine to serineInhibition of DNA replicationCysteine redox stateExposure to camptothecinCellular reducing systemsTargets of ROSIn silico predictionMutant proteinsRAD51 paralogsGenome stabilitySubcellular localizationNon-reducing SDS-PAGEDNA replicationIncreased electrophoretic mobilityMutated proteinChromatin fractionHR pathwayCamptothecin treatmentCysteine residuesInduce DNA damageHuman cellsCellular localizationCHO cells