2024
Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers
Huseman E, Lo A, Fedorova O, Elia J, Gueble S, Lin K, Sundaram R, Oh J, Liu J, Menges F, Rees M, Ronan M, Roth J, Batista V, Crawford J, Pyle A, Bindra R, Herzon S. Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers. Journal Of The American Chemical Society 2024, 146: 18241-18252. PMID: 38815248, PMCID: PMC11409917, DOI: 10.1021/jacs.3c06483.Peer-Reviewed Original ResearchDNA repair capacityDifferential DNA repair capacityDNA interstrand cross-linksRepair capacityInterstrand cross-linksDisplacement of fluorideDNA repairCross-linkingAberrant DNA repairLesionsHealthy tissueBrain cancerRing openingHealthy cellsMGMTSelective chemotherapyGenotoxic agentsTumorChemical DNA modificationsCancerMultistep processRepair
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
2018
Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair
Sulkowski PL, Sundaram RK, Oeck S, Corso CD, Liu Y, Noorbakhsh S, Niger M, Boeke M, Ueno D, Kalathil AN, Bao X, Li J, Shuch B, Bindra RS, Glazer PM. Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nature Genetics 2018, 50: 1086-1092. PMID: 30013182, PMCID: PMC6072579, DOI: 10.1038/s41588-018-0170-4.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksPGL/PCCDNA repair deficiency syndromeHomologous recombination DNA repair pathwayDNA repair pathwaysDouble-strand breaksHomologous recombination DNA repairSynthetic lethal targetingGenomic integrityDNA repairFumarate hydrataseMechanistic basisCancer predispositionFunction mutationsGermline lossKrebs cycleSuccinate dehydrogenaseHereditary paragangliomaRespectively1–3Ribose polymerase inhibitorsHereditary leiomyomatosisHereditary cancer syndromesCancer syndromesTumor cellsPolymerase inhibitors
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
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 factorCo-repression of mismatch repair gene expression by hypoxia in cancer cells: Role of the Myc/Max network
Bindra RS, Glazer PM. Co-repression of mismatch repair gene expression by hypoxia in cancer cells: Role of the Myc/Max network. Cancer Letters 2007, 252: 93-103. PMID: 17275176, DOI: 10.1016/j.canlet.2006.12.011.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingBasic Helix-Loop-Helix Leucine Zipper Transcription FactorsCell Cycle ProteinsCell HypoxiaCell Line, TumorDNA Mismatch RepairDown-RegulationGene Expression Regulation, NeoplasticGenomic InstabilityHumansHypoxia-Inducible Factor 1MutL Protein Homolog 1MutS Homolog 2 ProteinNeoplasmsNuclear ProteinsPromoter Regions, GeneticProto-Oncogene Proteins c-mycRepressor ProteinsConceptsHypoxia-inducible factorHypoxia-induced genetic instabilityGene expressionGenetic instabilityRepair genesStress response pathwaysC-Myc/MaxStress response factorsMismatch repair genesCancer cellsRepair gene expressionMax complexesCoordinated repressionKey genesDNA repairMMR pathwayProximal promoterMicroenvironmental stressMax networkMMR gene expressionDeficient cellsGenesRepressionEssential roleMMR genes
2006
CHK2-Dependent Phosphorylation of BRCA1 in Hypoxia
Gibson SL, Bindra RS, Glazer PM. CHK2-Dependent Phosphorylation of BRCA1 in Hypoxia. Radiation Research 2006, 166: 646-651. PMID: 17007555, DOI: 10.1667/rr0660.1.Peer-Reviewed Original ResearchConceptsCell cycle checkpoint regulationATM-dependent mannerChk2-dependent phosphorylationDNA repair factorsHypoxic stressCheckpoint kinaseCheckpoint regulationRepair factorsMammalian cellsDNA repairBRCA1 proteinDownstream targetsNovel roleChk2 expressionPhosphorylationChk2Pathway activationCritical roleBRCA1Diverse spectrumExpressionTumor microenvironmentActivationKinaseProtein
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 redistributionRepressionHypoxia-Induced Phosphorylation of Chk2 in an Ataxia Telangiectasia Mutated–Dependent Manner
Gibson SL, Bindra RS, Glazer PM. Hypoxia-Induced Phosphorylation of Chk2 in an Ataxia Telangiectasia Mutated–Dependent Manner. Cancer Research 2005, 65: 10734-10741. PMID: 16322218, DOI: 10.1158/0008-5472.can-05-1160.Peer-Reviewed Original ResearchConceptsDNA repairAtaxia telangiectasiaSerine/threonine kinaseDNA damageRelated kinase ATMKinase ataxia telangiectasiaNBS1-dependent mannerDNA repair factorsPhosphorylation of Chk2Hypoxic growth conditionsKinase ATMThreonine kinaseChk2 activationReplication forksRepair factorsChk2Apoptotic pathwayCell survivalNovel pathwayCycle arrestPhosphorylationGrowth conditionsDependent mannerPathwayCells
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