2020
Oncometabolites suppress DNA repair by disrupting local chromatin signalling
Sulkowski PL, Oeck S, Dow J, Economos NG, Mirfakhraie L, Liu Y, Noronha K, Bao X, Li J, Shuch BM, King MC, Bindra RS, Glazer PM. Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature 2020, 582: 586-591. PMID: 32494005, PMCID: PMC7319896, DOI: 10.1038/s41586-020-2363-0.Peer-Reviewed Original ResearchConceptsDNA repairDNA breaksFumarate hydrataseDownstream repair factorsHistone 3 lysine 9Homology-dependent repairPoly (ADP-ribose) polymeraseRecruitment of TIP60Deregulation of metabolismChromatin signalingSuccinate dehydrogenase genesGenome integrityLysine 9Repair factorsDehydrogenase geneEnd resectionIsocitrate dehydrogenase 1Aberrant hypermethylationMechanistic basisSomatic mutationsDehydrogenase 1GenesHuman malignanciesProper executionMutations
2019
Targeting DNA repair in gliomas.
Beckta JM, Bindra RS, Chalmers AJ. Targeting DNA repair in gliomas. Current Opinion In Neurology 2019, 32: 878-885. PMID: 31592790, DOI: 10.1097/wco.0000000000000760.Peer-Reviewed Original ResearchConceptsLocal controlPoor local controlBlood-brain barrierTreatment of gliomaOverall survivalSystemic treatmentClinical outcomesDismal prognosisAggressive entityPreclinical dataPatient outcomesRadiation therapyGliomasOutcomesDNA repair targetsTreatmentRepair mechanismsRepair targetsNovel chemoCurrent understandingPatientsPrognosisDNA damage responseMalignancy
2017
Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas
King AR, Corso CD, Chen EM, Song E, Bongiorni P, Chen Z, Sundaram RK, Bindra RS, Saltzman WM. Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas. Molecular Cancer Therapeutics 2017, 16: 1456-1469. PMID: 28566437, PMCID: PMC5545124, DOI: 10.1158/1535-7163.mct-16-0788.Peer-Reviewed Original ResearchConceptsHigh-grade gliomasPoor blood-brain barrier penetrationLocal disease progressionBlood-brain barrier penetrationEffect of radiotherapyIntrinsic pontine gliomaTreatment of glioblastomaMol Cancer TherCranial radiationDosing schedulesMultimodal treatmentIntracranial gliomasDisease progressionExtracranial tumorsPontine gliomaAggressive phenotypeRadiotherapy approachesGliomasMinimal toxicityRadiotherapyGlioblastomaBarrier penetrationTreatmentRadiosensitizerChemotherapy2-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
2016
A single double-strand break system reveals repair dynamics and mechanisms in heterochromatin and euchromatin
Janssen A, Breuer GA, Brinkman EK, van der Meulen AI, Borden SV, van Steensel B, Bindra RS, LaRocque JR, Karpen GH. A single double-strand break system reveals repair dynamics and mechanisms in heterochromatin and euchromatin. Genes & Development 2016, 30: 1645-1657. PMID: 27474442, PMCID: PMC4973294, DOI: 10.1101/gad.283028.116.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksHomologous recombinationGenome stabilityHeterochromatic DSBsEuchromatic DSBsSingle DNA double-strand breakMain DSB repair pathwaysDifferent chromatin domainsLarval imaginal discsDistinct nuclear domainsRepetitive DNA sequencesDSB repair pathwaysDouble-strand breaksChromatin contextChromatin domainsEuchromatic lociPericentromeric heterochromatinChromatin regionsHomologous chromosomesHR templateImaginal discsDSB repairDNA sequencesNuclear domainsRepair pathways
2015
Identification of Novel Radiosensitizers in a High-Throughput, Cell-Based Screen for DSB Repair Inhibitors
Goglia AG, Delsite R, Luz AN, Shahbazian D, Salem AF, Sundaram RK, Chiaravalli J, Hendrikx PJ, Wilshire JA, Jasin M, Kluger HM, Glickman JF, Powell SN, Bindra RS. Identification of Novel Radiosensitizers in a High-Throughput, Cell-Based Screen for DSB Repair Inhibitors. Molecular Cancer Therapeutics 2015, 14: 326-342. PMID: 25512618, PMCID: PMC4326563, DOI: 10.1158/1535-7163.mct-14-0765.Peer-Reviewed Original ResearchConceptsDSB repair inhibitorsDouble-strand breaksDSB repairHomologous recombinationRepair inhibitorsCell-based small molecule screenSuccessful DSB repairDNA-damaging agentsPlate-based formatCell-based screenSmall-molecule screenGenomic integrityTumor cell survivalMammalian cellsHR repairDNA repairMolecule screenReporter systemSecondary assaysCell survivalDNA damageCancer cell linesTumor cellsNovel hitsMost cancer therapies
2011
Targeted Disruption of the CCR5 Gene in Human Hematopoietic Stem Cells Stimulated by Peptide Nucleic Acids
Schleifman EB, Bindra R, Leif J, del Campo J, Rogers FA, Uchil P, Kutsch O, Shultz LD, Kumar P, Greiner DL, Glazer PM. Targeted Disruption of the CCR5 Gene in Human Hematopoietic Stem Cells Stimulated by Peptide Nucleic Acids. Cell Chemical Biology 2011, 18: 1189-1198. PMID: 21944757, PMCID: PMC3183429, DOI: 10.1016/j.chembiol.2011.07.010.Peer-Reviewed Original ResearchConceptsHematopoietic stem cellsHIV-1CCR5 geneHIV-1-infected individualsHIV-1 infectionGene modificationHIV-1 entryCCR5-Delta32 mutationImmune system functionStem cellsCCR5 knockoutMonths posttransplantationChemokine receptorsHuman hematopoietic stem cellsTherapeutic strategiesSubsequent engraftmentGenome modificationProtein levelsHuman cellsTargeted disruptionCCR5Peptide nucleic acidInfectionNucleic acidsCells
2010
Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130
Hegan DC, Lu Y, Stachelek GC, Crosby ME, Bindra RS, Glazer PM. Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 2201-2206. PMID: 20133863, PMCID: PMC2836641, DOI: 10.1073/pnas.0904783107.Peer-Reviewed Original ResearchMeSH KeywordsCell Line, TumorColonic NeoplasmsCrk-Associated Substrate ProteinDNA RepairDown-RegulationE2F4 Transcription FactorEnzyme InhibitorsGenes, BRCA1HumansPhenanthrenesPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesPromoter Regions, GeneticRad51 RecombinaseRadiation-Sensitizing AgentsRNA, Small InterferingConceptsHomology-dependent repairBase excision repair factorsExcision repair factorsPARP inhibitionRole of PARPPARP inhibitorsRepair factorsExpression of BRCA1DNA repairDNA breaksHypoxic cancer cellsRAD51SiRNA knockdownDNA damagePARP-1P130 expressionCancer therapyP130Cancer cellsPARPRad51 promoterHPV E7BRCA1E7 expressionSiRNAs
2009
Targeting the DNA damage response for cancer therapy
Powell SN, Bindra RS. Targeting the DNA damage response for cancer therapy. DNA Repair 2009, 8: 1153-1165. PMID: 19501553, DOI: 10.1016/j.dnarep.2009.04.011.Peer-Reviewed Original ResearchConceptsDNA damage responseCell cycle checkpointsDouble-strand breaksGenome integrityGenomic integrityHistone modificationsDamage responseCycle checkpointsDNA repairKey proteinsDNA damageAnti-cancer agentsHuman tumorsNew anti-cancer agentsPathwayCancer therapyTumor cellsCheckpointProteinTherapeutic interventionsRepairIntegrityDefectsCellsAppropriate response
2007
Regulation of DNA repair in hypoxic cancer cells
Bindra RS, Crosby ME, Glazer PM. Regulation of DNA repair in hypoxic cancer cells. Cancer And Metastasis Reviews 2007, 26: 249-260. PMID: 17415527, DOI: 10.1007/s10555-007-9061-3.Peer-Reviewed Original ResearchConceptsGenetic instabilityMismatch repairHypoxia-induced genetic instabilityDNA damage response factorsDamage response factorsDNA damage responseCellular stress responseATM/ATRDNA repair pathwaysHomologous recombination pathwayCancer cellsAcute DNA damage responseDNA mismatch repairTumor microenvironmental stressDamage responseKey genesHR repairDNA repairRepair pathwaysMicroenvironmental stressHypoxic cancer cellsStress responsePossible mechanistic explanationRecombination pathwayResponse factor
2006
Hypoxia-induced genetic instability—a calculated mechanism underlying tumor progression
Huang LE, Bindra RS, Glazer PM, Harris AL. Hypoxia-induced genetic instability—a calculated mechanism underlying tumor progression. Journal Of Molecular Medicine 2006, 85: 139-148. PMID: 17180667, DOI: 10.1007/s00109-006-0133-6.Peer-Reviewed Original ResearchRepression of RAD51 gene expression by E2F4/p130 complexes in hypoxia
Bindra RS, Glazer PM. Repression of RAD51 gene expression by E2F4/p130 complexes in hypoxia. Oncogene 2006, 26: 2048-2057. PMID: 17001309, DOI: 10.1038/sj.onc.1210001.Peer-Reviewed Original ResearchConceptsDNA repair pathwaysE2F siteRepair pathwaysHypoxia-induced genetic instabilityGenetic instabilityCoordinated transcriptional programRepair genesHypoxic stressRecombinational repair genesDownregulation of Rad51RAD51 gene expressionTranscriptional programsProximal promoterGene expressionNuclear accumulationMechanistic basisDNA mismatch repair genesRAD51BRCA1 promoterGenesPromoterMismatch repair genesBRCA1 geneNew therapeutic strategiesSimilar mechanism
2005
Hypoxia-Induced Down-regulation of BRCA1 Expression by E2Fs
Bindra RS, Gibson SL, Meng A, Westermark U, Jasin M, Pierce AJ, Bristow RG, Classon MK, Glazer PM. Hypoxia-Induced Down-regulation of BRCA1 Expression by E2Fs. Cancer Research 2005, 65: 11597-11604. PMID: 16357170, DOI: 10.1158/0008-5472.can-05-2119.Peer-Reviewed Original ResearchMeSH KeywordsBRCA1 ProteinBreast NeoplasmsCell HypoxiaChromatin ImmunoprecipitationColonic NeoplasmsDNA RepairDown-RegulationE2F Transcription FactorsGene Expression Regulation, NeoplasticHumansHypoxia-Inducible Factor 1, alpha SubunitLuciferasesLung NeoplasmsPromoter Regions, GeneticRecombination, GeneticReverse Transcriptase Polymerase Chain ReactionRNA, MessengerTranscription, GeneticTumor Cells, CulturedConceptsHomologous recombinationBRCA1 expressionGenetic instabilityError-prone NHEJ pathwayAdjacent E2F sitesHomologous recombination pathwayImpaired homologous recombinationNonhomologous end-joining repair pathwayGenetic mutationsTranscriptional repressionE2F sitePromoter occupancyTranscriptional responseDNA repairNHEJ pathwayRepair pathwaysNovel linkE2FRecombination pathwayBRCA1 promoterSporadic cancersIntriguing mechanismBRCA1 inactivationDynamic redistributionRepressionAlterations in DNA Repair Gene Expression under Hypoxia: Elucidating the Mechanisms of Hypoxia‐Induced Genetic Instability
BINDRA RS, SCHAFFER PJ, MENG A, WOO J, MÅSEIDE K, ROTH ME, LIZARDI P, HEDLEY DW, BRISTOW RG, GLAZER PM. Alterations in DNA Repair Gene Expression under Hypoxia: Elucidating the Mechanisms of Hypoxia‐Induced Genetic Instability. Annals Of The New York Academy Of Sciences 2005, 1059: 184-195. PMID: 16382054, DOI: 10.1196/annals.1339.049.Peer-Reviewed Original ResearchConceptsGenetic instabilityHomologous recombinationRAD51 expressionDNA repair gene expressionSuch genetic instabilityPost-hypoxic cellsDNA repair genesRepair gene expressionNumerous cell linesExpression of RAD51HR pathwayHR repairHypoxia-inducible factorGene expressionCell cycleRepair genesNovel mechanismHypoxic stressIndependent mannerPost-hypoxic periodCell linesCancer cellsCritical mediatorGenesExpressionHypoxia down-regulates DNA double strand break repair gene expression in prostate cancer cells
Meng AX, Jalali F, Cuddihy A, Chan N, Bindra RS, Glazer PM, Bristow RG. Hypoxia down-regulates DNA double strand break repair gene expression in prostate cancer cells. Radiotherapy And Oncology 2005, 76: 168-176. PMID: 16026872, DOI: 10.1016/j.radonc.2005.06.025.Peer-Reviewed Original ResearchConceptsProstate cancer cellsCell cycle distributionCancer cellsP53 genotypeCycle distributionProtein expressionRNA expressionPoor clinical outcomeInduction of hypoxiaMalignant prostate cell linesAbility of hypoxiaRepair genesProstate cell linesHypoxia-induced apoptosisHR-associated genesDouble-strand break repair genesClinical outcomesDNA double-strand break repair genesProstate cancerGene expressionIntratumoral hypoxiaVEGF expressionBPH-1Tumor cellsObserved genetic instabilityGenetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis
Bindra RS, Glazer PM. Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis. Mutation Research/Fundamental And Molecular Mechanisms Of Mutagenesis 2005, 569: 75-85. PMID: 15603753, DOI: 10.1016/j.mrfmmm.2004.03.013.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell HypoxiaDNA DamageDNA RepairGenomic InstabilityMutagenesisNeoplasmsOxidative StressConceptsGenetic instabilitySuch genetic instabilityDNA repair pathwaysOxidative base damageSuch DNA lesionsGenome integrityTumor microenvironmentRepair pathwaysDNA strand breaksDNA lesionsBase damageDNA damageStrand breaksMutagenesisInduction of mutagenesisAdverse conditionsTumor progressionMicroenvironmentRecent studiesSignificant threatPotential mechanismsNumerous typesInductionPathway
2004
Down-Regulation of Rad51 and Decreased Homologous Recombination in Hypoxic Cancer Cells
Bindra RS, Schaffer PJ, Meng A, Woo J, Måseide K, Roth ME, Lizardi P, Hedley DW, Bristow RG, Glazer PM. Down-Regulation of Rad51 and Decreased Homologous Recombination in Hypoxic Cancer Cells. Molecular And Cellular Biology 2004, 24: 8504-8518. PMID: 15367671, PMCID: PMC516750, DOI: 10.1128/mcb.24.19.8504-8518.2004.Peer-Reviewed Original ResearchMeSH KeywordsCell CycleDNA RepairDNA-Binding ProteinsDown-RegulationFemaleGene Expression RegulationHumansHypoxiaHypoxia-Inducible Factor 1Hypoxia-Inducible Factor 1, alpha SubunitIronMaleNuclear ProteinsProstatic NeoplasmsRecombination, GeneticRNA, MessengerTranscription FactorsTranscription, GeneticUterine Cervical NeoplasmsConceptsHomologous recombinationExpression of RAD51RAD51 expressionGenetic instabilityCancer cellsCritical DNA repair pathwaysDNA damage responseMultiple cancer cell typesDNA repair pathwaysLevels of RAD51Homologous recombination pathwayGene promoter activityTranscriptional repressionCell cycle profileCancer cell typesDamage responseMammalian cellsHypoxia-inducible factorDNA repairProtein stabilityRepair pathwaysAberrant regulationPromoter activityRAD51Hypoxic cancer cells
2003
Decreased Expression of the DNA Mismatch Repair Gene Mlh1 under Hypoxic Stress in Mammalian Cells
Mihaylova VT, Bindra RS, Yuan J, Campisi D, Narayanan L, Jensen R, Giordano F, Johnson RS, Rockwell S, Glazer PM. Decreased Expression of the DNA Mismatch Repair Gene Mlh1 under Hypoxic Stress in Mammalian Cells. Molecular And Cellular Biology 2003, 23: 3265-3273. PMID: 12697826, PMCID: PMC153206, DOI: 10.1128/mcb.23.9.3265-3273.2003.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdenosine TriphosphatasesAnimalsBase Pair MismatchBeta-GalactosidaseCarrier ProteinsCell HypoxiaCells, CulturedDeferoxamineDinucleotide RepeatsDNA RepairDNA Repair EnzymesDNA-Binding ProteinsEnzyme InhibitorsFibroblastsGenes, ReporterHeLa CellsHumansHydroxamic AcidsHypoxia-Inducible Factor 1, alpha SubunitIron Chelating AgentsMethylationMiceMice, TransgenicMismatch Repair Endonuclease PMS2MutL Protein Homolog 1MutS Homolog 2 ProteinNeoplasm ProteinsNuclear ProteinsProto-Oncogene ProteinsRNA, MessengerTranscription FactorsConceptsGenetic instabilityMammalian cellsDNA mismatch repair genes MLH1Chromosomal reporter geneHistone deacetylase inhibitor trichostatin AStationary-phase mutagenesisDeacetylase inhibitor trichostatin AInhibitor trichostatin AMismatch repair genes MLH1Treatment of cellsHistone deacetylationStress signalsKey MMR proteinsReporter geneGenes MLH1Gene expressionLow oxygen tensionPMS2 levelsMMR gene expressionTrichostatin AMLH1 mRNAPotential new pathwaysDinucleotide repeatsHeterodimer partnerHypoxia-induced reduction