2023
Acetylation of MLH1 by CBP increases cellular DNA mismatch repair activity
Zhang M, Zhao J, Glazer P, Bai W, Bepler G, Zhang X. Acetylation of MLH1 by CBP increases cellular DNA mismatch repair activity. The Journal Of Biochemistry 2023, 174: 183-191. PMID: 37094360, DOI: 10.1093/jb/mvad034.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationCREB-Binding ProteinDNADNA Mismatch RepairDNA RepairProtein Processing, Post-TranslationalConceptsMutLα complexMMR activityUbiquitin-proteasome degradation pathwayDNA mismatch repair activityDNA damage responsePost-translational modificationsCell cycle checkpointsOverexpression of CBPMismatch repair activityDNA base pair mismatchesInsertions/deletionsDNA mismatch repair proteinsGenomic integrityDamage responseDNA replicationCycle checkpointsRepair proteinsTrichostatin ABase pair mismatchesNovel roleMismatch repair proteinsRepair activityCBPProteinDeacetylase inhibitors
2022
Metastatic and multiply relapsed SDH‐deficient GIST and paraganglioma displays clinical response to combined poly ADP‐ribose polymerase inhibition and temozolomide
Singh C, Bindra RS, Glazer PM, Vasquez JC, Pashankar F. Metastatic and multiply relapsed SDH‐deficient GIST and paraganglioma displays clinical response to combined poly ADP‐ribose polymerase inhibition and temozolomide. Pediatric Blood & Cancer 2022, 70: e30020. PMID: 36151992, DOI: 10.1002/pbc.30020.Peer-Reviewed Original Research
2021
Vulnerability of IDH1-Mutant Cancers to Histone Deacetylase Inhibition via Orthogonal Suppression of DNA Repair
Dow J, Krysztofiak A, Liu Y, Colon-Rios DA, Rogers FA, Glazer PM. Vulnerability of IDH1-Mutant Cancers to Histone Deacetylase Inhibition via Orthogonal Suppression of DNA Repair. Molecular Cancer Research 2021, 19: 2057-2067. PMID: 34535560, PMCID: PMC8642278, DOI: 10.1158/1541-7786.mcr-21-0456.Peer-Reviewed Original ResearchConceptsHistone deacetylase inhibitor vorinostatPatient-derived tumor xenograftsHomology-directed repairIsocitrate dehydrogenase 1/2 mutationsHistone deacetylase inhibitionIDH1 mutant cellsGreater cell deathHDACi treatmentInhibitor vorinostatTumor xenograftsDeacetylase inhibitionIDH1/2 mutationsPotential biomarkersSpecific cancersMutant cancersCancerCancer cellsDNA repair defectsMalignancyVorinostatDNA double-strand breaksGliomasHistone hypermethylationCell deathPARPiRegulation of the Cell-Intrinsic DNA Damage Response by the Innate Immune Machinery
Hayman TJ, Glazer PM. Regulation of the Cell-Intrinsic DNA Damage Response by the Innate Immune Machinery. International Journal Of Molecular Sciences 2021, 22: 12761. PMID: 34884568, PMCID: PMC8657976, DOI: 10.3390/ijms222312761.Peer-Reviewed Original ResearchMeSH KeywordsDNA DamageDNA RepairHumansImmunity, InnateMembrane ProteinsNucleotidyltransferasesSignal TransductionConceptsDNA double-strand breaksInnate immune machineryGenomic integrityDNA-damaging therapiesDNA damage response systemDNA DSB repair pathwaysImmune machineryCell-autonomous responsesDNA damage responseDSB repair pathwaysDouble-strand breaksDamage responseInnate immune pathwaysRepair pathwaysCell survivalDNA damageUnderappreciated roleProper repairImmune pathwaysMachineryPathwayAdaptive immune responsesSignificant normal tissue toxicityMost therapeutic studiesImmune responseBBIT20 inhibits homologous DNA repair with disruption of the BRCA1–BARD1 interaction in breast and ovarian cancer
Raimundo L, Paterna A, Calheiros J, Ribeiro J, Cardoso DSP, Piga I, Neto SJ, Hegan D, Glazer PM, Indraccolo S, Mulhovo S, Costa JL, Ferreira M, Saraiva L. BBIT20 inhibits homologous DNA repair with disruption of the BRCA1–BARD1 interaction in breast and ovarian cancer. British Journal Of Pharmacology 2021, 178: 3627-3647. PMID: 33899955, PMCID: PMC9124438, DOI: 10.1111/bph.15506.Peer-Reviewed Original ResearchConceptsTriple-negative breastOvarian cancerXenograft mouse modelMouse modelAntitumour activityAdvanced ovarian cancerCancer cellsPatient-derived cell linesHomologous DNA repairOvarian cancer cellsNon-malignant cellsPatient-derived cellsMarked synergistic effectAvailable therapiesCombination therapyCell cycle arrestReactive oxygen species generationSide effectsDNA repair-related genesSingle agentTherapeutic outcomesCancerOxygen species generationPersonalized treatmentResistant cancers
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
Impact of hypoxia on DNA repair and genome integrity
Kaplan AR, Glazer PM. Impact of hypoxia on DNA repair and genome integrity. Mutagenesis 2019, 35: 61-68. PMID: 31282537, PMCID: PMC7317153, DOI: 10.1093/mutage/gez019.Peer-Reviewed Original ResearchConceptsDNA repairDNA repair pathwaysHomology-directed repairBase excision repairGenome integrityRepair pathwaysGenomic instabilityExcision repairHypoxia mimeticMismatch repairDiverse mechanismsImpact of hypoxiaCancer progressionMutation frequencyTumor biologyTumor microenvironmentDevelopment of metastasesPotential clinical relevanceProfound effectRepairBiologyHypoxiaPathwayHallmarkMicroenvironmentCediranib 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
2017
A cell-penetrating antibody inhibits human RAD51 via direct binding
Turchick A, Hegan DC, Jensen RB, Glazer PM. A cell-penetrating antibody inhibits human RAD51 via direct binding. Nucleic Acids Research 2017, 45: 11782-11799. PMID: 29036688, PMCID: PMC5714174, DOI: 10.1093/nar/gkx871.Peer-Reviewed Original ResearchConceptsHomology-directed repairMolecular basisDirect bindingSynthetic lethal killingPre-clinical developmentBRCA2-deficient cancer cellsCell-penetrating antibodiesAnti-cancer agentsLupus autoantibodiesHuman Rad51DNA repairDNA bindingRAD51N-terminusCancer cellsSilico molecular modelingFunction mutationsCancer therapySpecific inhibitorDNANovel inhibitorsAttractive targetComplementarity-determining regionsMolecular modelingCell penetration2-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
2001
Triplex forming oligonucleotides: sequence-specific tools for gene targeting
Knauert M, Glazer P. Triplex forming oligonucleotides: sequence-specific tools for gene targeting. Human Molecular Genetics 2001, 10: 2243-2251. PMID: 11673407, DOI: 10.1093/hmg/10.20.2243.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsHuman gene therapyGene therapy agentsAbility of TFOsTriplex formingGenome modificationGene therapyMammalian cellsGenetic manipulationGene targetingGene expressionPotential applicationsGenetic targetingDuplex DNATherapy agentsMajor grooveLoose canonsHigh specificityGenesRecent studiesTargetingRelated moleculesTFOCellsDevicesDNAHypermutability to ionizing radiation in mismatch repair-deficient, Pms2 knockout mice.
Xu X, Narayanan L, Dunklee B, Liskay R, Glazer P. Hypermutability to ionizing radiation in mismatch repair-deficient, Pms2 knockout mice. Cancer Research 2001, 61: 3775-80. PMID: 11325851.Peer-Reviewed Original ResearchConceptsMismatch repairSimple sequence repeatsWild-type transgenic miceCell linesLambda cII geneMutation frequencyDNA mismatch repairHigher clonogenic survivalMMR-deficient miceLambda shuttle vectorTolerance phenotypeSequence repeatsPatterns of IRReporter geneRepeat sequencesMononucleotide repeat sequencesShuttle vectorSingle bp deletionCII geneNullizygous animalsNullizygous miceHypermutabilityBp deletionWild-type miceClonogenic survivalGenomic Instability in Cancer
Rockwell S, Yuan J, Peretz S, Glazer P. Genomic Instability in Cancer. Novartis Foundation Symposia 2001, 240: 133-151. PMID: 11727926, DOI: 10.1002/0470868716.ch9.Peer-Reviewed Original ResearchConceptsGenomic instabilityChromosomal fragile sitesExposure of cellsNutrient deprivationDNA repairGenomic rearrangementsSelection pressureDNA overreplicationGene expressionGenetic changesFragile sitesGenetic heterogeneityCell proliferationGene amplificationCell populationsBenign cell populationsMutation frequencyHypoxic environmentAggressive phenotypeSolid tumorsExpressionOverreplicationCellsAdverse microenvironmentCytogenetic changesGene targeting via triple-helix formation
Casey B, Glazer P. Gene targeting via triple-helix formation. Progress In Nucleic Acid Research And Molecular Biology 2001, 67: 163-192. PMID: 11525382, DOI: 10.1016/s0079-6603(01)67028-4.Peer-Reviewed Original Research
2000
Ionizing radiation-induced apoptosis via separate Pms2- and p53-dependent pathways.
Zeng M, Narayanan L, Xu X, Prolla T, Liskay R, Glazer P. Ionizing radiation-induced apoptosis via separate Pms2- and p53-dependent pathways. Cancer Research 2000, 60: 4889-93. PMID: 10987303.Peer-Reviewed Original ResearchMutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts
Andrew S, Xu X, Baross-Francis A, Narayanan L, Milhausen K, Liskay R, Jirik F, Glazer P. Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts. Carcinogenesis 2000, 21: 1291-1296. PMID: 10874005, DOI: 10.1093/carcin/21.7.1291.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphatasesAnimalsBase Pair MismatchCrosses, GeneticDNA RepairDNA Repair EnzymesDNA-Binding ProteinsFemaleFrameshift MutationGenes, ReporterGenotypeGerm-Line MutationMaleMiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutMice, TransgenicMismatch Repair Endonuclease PMS2MutagenesisMutS Homolog 2 ProteinPoint MutationProteinsProto-Oncogene ProteinsConceptsPms2-deficient miceMsh2-deficient miceHereditary non-polyposis colorectal cancer patientsCII target geneDNA mismatch repair deficiencyColorectal cancer patientsPMS2 germline mutationsMismatch repair deficiencyReporter transgenic miceMutation frequencyLacI target geneCancer patientsTarget genesMouse modelKnockout miceTumor spectrumTransgenic miceFrameshift mutationGermline mutationsMiceRepair deficiencyPMS2 deficiencySupF target geneMSH2Predominant mutationsTriple-Helix Formation Induces Recombination in Mammalian Cells via a Nucleotide Excision Repair-Dependent Pathway
Faruqi A, Datta H, Carroll D, Seidman M, Glazer P. Triple-Helix Formation Induces Recombination in Mammalian Cells via a Nucleotide Excision Repair-Dependent Pathway. Molecular And Cellular Biology 2000, 20: 990-1000. PMID: 10629056, PMCID: PMC85216, DOI: 10.1128/mcb.20.3.990-1000.2000.Peer-Reviewed Original ResearchAnimalsBase SequenceCell Line, TransformedChromosome MappingColonic NeoplasmsCOS CellsDNA RepairDNA-Binding ProteinsGenes, ReporterGenes, SuppressorHumansModels, GeneticMutagenesisNucleic Acid ConformationOligodeoxyribonucleotidesRecombinant ProteinsRecombination, GeneticRNA, TransferRNA-Binding ProteinsSequence DeletionTransfectionTumor Cells, CulturedXeroderma Pigmentosum Group A Protein
1999
Different mutator phenotypes in Mlh1- versus Pms2-deficient mice
Yao X, Buermeyer A, Narayanan L, Tran D, Baker S, Prolla T, Glazer P, Liskay R, Arnheim N. Different mutator phenotypes in Mlh1- versus Pms2-deficient mice. Proceedings Of The National Academy Of Sciences Of The United States Of America 1999, 96: 6850-6855. PMID: 10359802, PMCID: PMC22005, DOI: 10.1073/pnas.96.12.6850.Peer-Reviewed Original ResearchConceptsMismatch repairMutator phenotypeMutation rateDifferent chromosomal locationsSingle-molecule PCRDinucleotide repeat lociMutation frequencyDNA mismatch repairMononucleotide repeat tractsChromosomal locationCellular processesDNA repair capacityHigh mutation frequencyDifferent mutator phenotypesMultiple genetic alterationsKnockout strainRepeat tractMlh1pMLH1 MMR geneRepeat lociGenetic alterationsDifferent tumor spectrumRepair capacityTumor developmentMMR genesTargeted Correction of an Episomal Gene in Mammalian Cells by a Short DNA Fragment Tethered to a Triplex-forming Oligonucleotide*
Chan P, Lin M, Faruqi A, Powell J, Seidman M, Glazer P. Targeted Correction of an Episomal Gene in Mammalian Cells by a Short DNA Fragment Tethered to a Triplex-forming Oligonucleotide*. Journal Of Biological Chemistry 1999, 274: 11541-11548. PMID: 10206960, DOI: 10.1074/jbc.274.17.11541.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceCell LineCOS CellsDNADNA RepairHumansIndicators and ReagentsPlasmidsPoint MutationConceptsMammalian cellsGene correctionSV40 shuttle vectorTriplex motifNucleotide excision repairSequence-specific mannerEpisomal geneSupF reporter geneXPA cDNASpecific target sitesGene conversionShort DNA fragmentsDNA repairGene targetingTarget genesDNA segmentsReporter geneExcision repairDNA fragmentsBifunctional oligonucleotidesShuttle vectorSequence conversionGenesSV40 vectorsFlexible linker
1997
Role of DNA mismatch repair in the cytotoxicity of ionizing radiation.
Fritzell J, Narayanan L, Baker S, Bronner C, Andrew S, Prolla T, Bradley A, Jirik F, Liskay R, Glazer P. Role of DNA mismatch repair in the cytotoxicity of ionizing radiation. Cancer Research 1997, 57: 5143-7. PMID: 9371516.Peer-Reviewed Original ResearchConceptsMammalian cellsCellular responsesCell linesTranscription-coupled repairMMR systemWild-type cellsDNA-damaging agentsWild-type cell linesMMR-deficient cellsDNA mismatch repairDNA mismatch repair systemMismatch repair systemActive genesFutile repairMMR factorsAlkylation damageMismatch repairReplication errorsDNA damageRepair systemRelated miceCancer cellsClonogenic survivalMMR genesGenes