2024
Global screening of base excision repair in nucleosome core particles
Sutton T, Sawyer D, Naila T, Sweasy J, Tomkinson A, Delaney S. Global screening of base excision repair in nucleosome core particles. DNA Repair 2024, 144: 103777. PMID: 39476546, DOI: 10.1016/j.dnarep.2024.103777.Peer-Reviewed Original ResearchBase excision repairUracil-DNA glycosylaseAP endonuclease 1Nucleosome core particleBase excision repair enzymesAbsence of chromatin remodelingExcision repairDNA polymerase BGenome wide mappingContext of chromatinEukaryotic genomic DNADNA damageCore particlesPolymerase BChromatin remodelingActivities of BER enzymesNick siteGenomic DNAProtein interactionsMutational hotspotsNucleosomal DNADNA glycosylaseGenomic instabilityCellular factorsEntry/exit regionCollapsed State Mediates the Low Fidelity of the DNA Polymerase β I260 Mutant
Fijen C, Chavira C, Alnajjar K, Sawyer D, Sweasy J. Collapsed State Mediates the Low Fidelity of the DNA Polymerase β I260 Mutant. Biochemistry 2024, 63: 2414-2424. PMID: 39299701, PMCID: PMC11448664, DOI: 10.1021/acs.biochem.4c00263.Peer-Reviewed Original ResearchPol-BI260MForster resonance energy transferNucleotide discriminationConformational changesDNA polymerase BTemperature-sensitive mutationAccurate DNA synthesisReduced fidelityBase excision repairContext-dependent mannerPolymerase BNoncovalent stepPolymerase fidelityBound nucleotideResonance energy transferIncreased mutagenesisGenomic instabilityFinger regionWT proteinExcision repairI260Rate of conformational changeTurnover kineticsMolecular mechanismsModifying the Basicity of the dNTP Leaving Group Modulates Precatalytic Conformational Changes of DNA Polymerase β
Alnajjar K, Wang K, Alvarado-Cruz I, Chavira C, Negahbani A, Nakhjiri M, Minard C, Garcia-Barboza B, Kashemirov B, McKenna C, Goodman M, Sweasy J. Modifying the Basicity of the dNTP Leaving Group Modulates Precatalytic Conformational Changes of DNA Polymerase β. Biochemistry 2024, 63: 1412-1422. PMID: 38780930, PMCID: PMC11155676, DOI: 10.1021/acs.biochem.4c00065.Peer-Reviewed Original ResearchDNA polymerase BPolymerase BPol-BBase excision DNA repair pathwayLinear free energy relationshipGapped DNA substratesRemoval of damaged DNA basesFree energy relationshipConformational changesChemical transition stateAccumulation of mutationsDNA repair pathwaysDamaged DNA basesGroup basicityCorrect nucleotideDNA substratesIncoming nucleotideTransition stateEnergy relationshipFingers subdomainRepair pathwaysSubstrate selectivityNucleotideTriphosphate moietyCatalytic functionD239Y germline variant of NTHL1 glycosylase increases susceptibility to colorectal cancer in mice
Masannat T, Ghishan F, Kiela P, Sweasy J. D239Y germline variant of NTHL1 glycosylase increases susceptibility to colorectal cancer in mice. Physiology 2024, 39: 2118. DOI: 10.1152/physiol.2024.39.s1.2118.Peer-Reviewed Original ResearchInflammation-associated colorectal cancerColorectal cancerDistal colonColon lengthSusceptibility to colorectal cancerC57BL/6 wild-typeMicronucleated normochromatic erythrocytesProximal tumor locationFemale C57BL/6 wild-typeIncreased lifetime riskDextran sulfate sodiumSize of polypsMonitoring body weightKnock-in miceIncreased polyp numberDominant-negative mutationsNormal drinking waterDSS cycleTumor locationWT miceNormochromatic erythrocytesDNA damageWT littermatesColitis scoresRepair mechanismsTemporal coordination of the transcription factor response to H2O2 stress
Jose E, March-Steinman W, Wilson B, Shanks L, Parkinson C, Alvarado-Cruz I, Sweasy J, Paek A. Temporal coordination of the transcription factor response to H2O2 stress. Nature Communications 2024, 15: 3440. PMID: 38653977, PMCID: PMC11039679, DOI: 10.1038/s41467-024-47837-w.Peer-Reviewed Original ResearchConceptsGroup of transcription factorsTranscription factorsResponse to H2O2 stressTranscription factor activityCell cycle arrestDose-dependent outcomeRepair oxidative damageOxidative stressDose-dependent activationTime-lapse imagingH2O2 stressCell deathRestoring redox balanceDose-dependentlyTranscriptionRedox balanceGlucose oxidase enzymeNF-kBFactor activity
2020
Role of cysteines in the structure and function of 8-oxoguanine DNA glycosylase
Wang K, Alnajjar K, Maayah M, Sweasy J. Role of cysteines in the structure and function of 8-oxoguanine DNA glycosylase. 2020 DOI: 10.1021/scimeetings.0c07078.Peer-Reviewed Original Research
2017
Defective Nucleotide Release by DNA Polymerase β Mutator Variant E288K Is the Basis of Its Low Fidelity
Mahmoud MM, Schechter A, Alnajjar KS, Huang J, Towle-Weicksel J, Eckenroth BE, Doublié S, Sweasy JB. Defective Nucleotide Release by DNA Polymerase β Mutator Variant E288K Is the Basis of Its Low Fidelity. Biochemistry 2017, 56: 5550-5559. PMID: 28945359, PMCID: PMC5654646, DOI: 10.1021/acs.biochem.7b00869.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SubstitutionBiocatalysisColonic NeoplasmsDNADNA Polymerase betaDNA RepairDNA ReplicationEnzyme StabilityFluorescent DyesHumansKineticsModels, MolecularMutagenesis, Site-DirectedMutationNaphthalenesulfonatesNeoplasm ProteinsP-DimethylaminoazobenzeneProtein ConformationProtein Interaction Domains and MotifsProtein RefoldingRecombinant ProteinsSubstrate SpecificityDNA Polymerase β Cancer-Associated Variant I260M Exhibits Nonspecific Selectivity toward the β–γ Bridging Group of the Incoming dNTP
Alnajjar KS, Negahbani A, Nakhjiri M, Krylov IS, Kashemirov BA, McKenna CE, Goodman MF, Sweasy JB. DNA Polymerase β Cancer-Associated Variant I260M Exhibits Nonspecific Selectivity toward the β–γ Bridging Group of the Incoming dNTP. Biochemistry 2017, 56: 5449-5456. PMID: 28862868, PMCID: PMC5634933, DOI: 10.1021/acs.biochem.7b00713.Peer-Reviewed Original ResearchDNA repair and systemic lupus erythematosus
Meas R, Burak MJ, Sweasy JB. DNA repair and systemic lupus erythematosus. DNA Repair 2017, 56: 174-182. PMID: 28623091, PMCID: PMC5543809, DOI: 10.1016/j.dnarep.2017.06.020.Peer-Reviewed Original ResearchConceptsSystemic lupus erythematosusDevelopment of lupusLupus erythematosusGenetic predispositionChronic autoimmune diseaseAutoimmune diseasesMonozygotic twin concordanceFamilial aggregation studiesImmune systemLupusPotential associationCommon risk allelesRisk allelesDNA repair genesEnvironmental exposuresAberrant DNA repairErythematosusDNA repairTwin concordanceRepair genesCurrent knowledgeRepairAggregation studiesPredispositionDiseaseA Change in the Rate-Determining Step of Polymerization by the K289M DNA Polymerase β Cancer-Associated Variant
Alnajjar KS, Garcia-Barboza B, Negahbani A, Nakhjiri M, Kashemirov B, McKenna C, Goodman MF, Sweasy JB. A Change in the Rate-Determining Step of Polymerization by the K289M DNA Polymerase β Cancer-Associated Variant. Biochemistry 2017, 56: 2096-2105. PMID: 28326765, PMCID: PMC5522186, DOI: 10.1021/acs.biochem.6b01230.Peer-Reviewed Original ResearchDNA Polymerase Beta Germline Variant Confers Cellular Response to Cisplatin Therapy
Nemec AA, Abriola L, Merkel JS, de Stanchina E, DeVeaux M, Zelterman D, Glazer PM, Sweasy JB. DNA Polymerase Beta Germline Variant Confers Cellular Response to Cisplatin Therapy. Molecular Cancer Research 2017, 15: 269-280. PMID: 28074003, PMCID: PMC5334281, DOI: 10.1158/1541-7786.mcr-16-0227-t.Peer-Reviewed Original ResearchConceptsPrognostic biomarker potentialMouse xenograft modelLung cancer cellsPoor prognosisTreatment of cancerLung cancerSpecific chemotherapyXenograft modelPromising biomarkerMouse xenograftsMutational statusCancer ResChemotherapyGermline mutationsNucleotide excision repair pathwayBiomarker potentialCancer chemotherapyCancer treatmentCarrier statusCisplatinCancer cellsTumorsCancerTreatmentCell death
2016
The Tumor-Associated Variant RAD51 G151D Induces a Hyper-Recombination Phenotype
Marsden CG, Jensen RB, Zagelbaum J, Rothenberg E, Morrical SW, Wallace SS, Sweasy JB. The Tumor-Associated Variant RAD51 G151D Induces a Hyper-Recombination Phenotype. PLOS Genetics 2016, 12: e1006208. PMID: 27513445, PMCID: PMC4981402, DOI: 10.1371/journal.pgen.1006208.Peer-Reviewed Original ResearchMeSH KeywordsBRCA2 ProteinBreast NeoplasmsChromosome AberrationsDNA Breaks, Double-StrandedDNA DamageDNA RepairDoxorubicinFemaleGene Expression Regulation, NeoplasticGenomic InstabilityHumansMCF-7 CellsMitomycinMutationRad51 RecombinaseRadiation, IonizingRecombinational DNA RepairSister Chromatid ExchangeConceptsHuman breast epithelial cellsBreast epithelial cellsSister chromatid exchangesBreast carcinomaDrug resistanceMitomycin CEpithelial cellsChromosomal aberrationsHigh levelsChromatid exchangesRepairSomatic variantsRAD51 variantsDNA damageMultiple DNA damaging agentsDNA damaging agentsPresence of RPAPhenotypeCellsCarcinomaExpressionDNA double-strand breaksDamaging agentsLevelsVariants
2014
Mutation of POLB Causes Lupus in Mice
Senejani AG, Liu Y, Kidane D, Maher SE, Zeiss CJ, Park HJ, Kashgarian M, McNiff JM, Zelterman D, Bothwell AL, Sweasy JB. Mutation of POLB Causes Lupus in Mice. Cell Reports 2014, 6: 1-8. PMID: 24388753, PMCID: PMC3916967, DOI: 10.1016/j.celrep.2013.12.017.Peer-Reviewed Original ResearchConceptsSystemic lupus erythematosusLupus-like diseaseLupus erythematosusAutoimmune pathologyMouse modelGenome-wide association studiesPol β activityDecreased expressionMutant miceUnderlying causeMicePrevious genome-wide association studyΒ activityDNA polymerase activityReplication studyExcision repair pathwayImmune diversitySomatic hypermutationBase excision repair pathwayAssociation studiesErythematosusLupusPolymerase activityExpressionKey enzyme
2012
Y265C DNA polymerase beta knockin mice survive past birth and accumulate base excision repair intermediate substrates
Senejani AG, Dalal S, Liu Y, Nottoli TP, McGrath JM, Clairmont CS, Sweasy JB. Y265C DNA polymerase beta knockin mice survive past birth and accumulate base excision repair intermediate substrates. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 6632-6637. PMID: 22493258, PMCID: PMC3340078, DOI: 10.1073/pnas.1200800109.Peer-Reviewed Original ResearchConceptsDNA polymerase activityWT littermatesKnockin miceMiceMouse embryo fibroblastsChromosomal aberrationsWT mouse embryo fibroblastsNormal Mendelian ratioSlow proliferationPolymerase activityBirthΒ variantCell deathEmbryo fibroblastsWT cellsExcision repair pathwayDNA repair systemsCellular metabolismBase excision repair pathwayFibroblastsHoursHigh levelsHomozygous mutantsKey players
2004
Is there a link between DNA polymerase beta and cancer?
Starcevic D, Dalal S, Sweasy J. Is there a link between DNA polymerase beta and cancer? Cell Cycle 2004, 3: 998-1001. PMID: 15280658.Peer-Reviewed Original Research