Featured Publications
BRCA2 BRC missense variants disrupt RAD51-dependent DNA repair
Jimenez-Sainz J, Mathew J, Moore G, Lahiri S, Garbarino J, Eder JP, Rothenberg E, Jensen RB. BRCA2 BRC missense variants disrupt RAD51-dependent DNA repair. ELife 2022, 11: e79183. PMID: 36098506, PMCID: PMC9545528, DOI: 10.7554/elife.79183.Peer-Reviewed Original ResearchConceptsHomology-directed repairDNA double-strand breaksFork protectionReplication fork protectionRad51 nucleoprotein filamentsMissense mutationsSingle amino acid substitutionRad51-ssDNA complexesDouble-strand breaksUnknown functional consequencesBRCA2 VUSAmino acid substitutionsGenome stabilityNucleoprotein filamentDNA repairRepeat regionSpacer regionBRCA2 proteinBenign allelesCellular responsesAcid substitutionsFunctional consequencesFrameshift mutationGene predisposeBRC2The Pathogenic R3052W BRCA2 Variant Disrupts Homology-Directed Repair by Failing to Localize to the Nucleus
Jimenez-Sainz J, Krysztofiak A, Garbarino J, Rogers F, Jensen RB. The Pathogenic R3052W BRCA2 Variant Disrupts Homology-Directed Repair by Failing to Localize to the Nucleus. Frontiers In Genetics 2022, 13: 884210. PMID: 35711920, PMCID: PMC9197106, DOI: 10.3389/fgene.2022.884210.Peer-Reviewed Original ResearchDominant-negative alleleDNA damage responseDNA repair functionDNA strand exchangeHomology-directed repairGenome instabilityCellular functionsDamage responseDNA bindingNegative allelesStrand exchangeRepair functionGermline missense variantsCell survivalFunction mutationsMissense variantsRAD51Pathogenic allelesSimple lossPARP inhibitorsCytoplasmProteinAllelesHomologyDNAPolymerase θ Coordinates Multiple Intrinsic Enzymatic Activities during DNA Repair
Zahn KE, Jensen RB. Polymerase θ Coordinates Multiple Intrinsic Enzymatic Activities during DNA Repair. Genes 2021, 12: 1310. PMID: 34573292, PMCID: PMC8470613, DOI: 10.3390/genes12091310.Peer-Reviewed Original ResearchConceptsPolymerase θAmino acid protein productDNA double-strand break repair pathwayDouble-strand break repair pathwayTemplate-dependent DNA polymerasesDNA-dependent ATPaseDNA double-strand breaksBreak repair pathwayIntrinsic enzymatic activitySynthetic lethal strategyDouble-strand breaksDrug target candidatesDNA repair defectsDNA polymerase θSmall molecule inhibitorsPARP inhibitor resistanceHomologous recombinationDNA repairLyase functionRepair pathwaysEnzymatic functionProtein productsLethal strategiesRepair defectsBRCA-mutant cancersLoss of ATRX confers DNA repair defects and PARP inhibitor sensitivity
Garbarino J, Eckroate J, Sundaram RK, Jensen RB, Bindra RS. Loss of ATRX confers DNA repair defects and PARP inhibitor sensitivity. Translational Oncology 2021, 14: 101147. PMID: 34118569, PMCID: PMC8203843, DOI: 10.1016/j.tranon.2021.101147.Peer-Reviewed Original ResearchPARP inhibitor sensitivityInhibitor sensitivityKey DNA damage response pathwaysDNA damage response pathwayFunction of ATRXHR-defective cellsDamage response pathwayAlpha thalassemia/mental retardation syndrome XDNA repair defectsLoss of ATRXHistone chaperonesHistone variantsReplication stressMental retardation syndrome XModel cell lineResponse pathwaysEpistatic interactionsDNA repairGene targetingAtaxia telangiectasiaKO cellsIsocitrate dehydrogenase 1DDR defectsMolecular markersRepair defectsImprecise Medicine: BRCA2 Variants of Uncertain Significance (VUS), the Challenges and Benefits to Integrate a Functional Assay Workflow with Clinical Decision Rules
Jimenez-Sainz J, Jensen RB. Imprecise Medicine: BRCA2 Variants of Uncertain Significance (VUS), the Challenges and Benefits to Integrate a Functional Assay Workflow with Clinical Decision Rules. Genes 2021, 12: 780. PMID: 34065235, PMCID: PMC8161351, DOI: 10.3390/genes12050780.Peer-Reviewed Original ResearchConceptsCancer riskFunctional assaysUncertain significanceSomatic BRCA2 mutationClinical decision ruleFuture cancer riskClinical decision processBRCA2 VUSBiochemical functional assaysClinical findingsTherapeutic optionsTreatment optionsPancreatic cancerBRCA2 mutationsClinical guidancePlatinum agentsPathological outcomesBenign naturePARP inhibitorsBRCA2 genesGermline mutationsPathological impactAccurate functional assaysBRCA2 variantsPatientsHuman DNA polymerase θ harbors DNA end-trimming activity critical for DNA repair
Zahn KE, Jensen RB, Wood RD, Doublié S. Human DNA polymerase θ harbors DNA end-trimming activity critical for DNA repair. Molecular Cell 2021, 81: 1534-1547.e4. PMID: 33577776, PMCID: PMC8231307, DOI: 10.1016/j.molcel.2021.01.021.Peer-Reviewed Original ResearchDNA Strand Exchange to Monitor Human RAD51-Mediated Strand Invasion and Pairing
Lahiri S, Jensen RB. DNA Strand Exchange to Monitor Human RAD51-Mediated Strand Invasion and Pairing. Methods In Molecular Biology 2020, 2153: 101-113. PMID: 32840775, PMCID: PMC10434838, DOI: 10.1007/978-1-0716-0644-5_8.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksDNA strand exchangeStrand invasionSingle-strand DNA gapsStrand exchangeDNA DSBsHuman Rad51 proteinDNA strand exchange reactionDouble-strand breaksHomologous recombination pathwayHigh-fidelity repairStrand exchange reactionGenomic integrityRad51 proteinReplication forksDNA substratesHomology searchDNA gapsGenetic informationMitotic cellsRecombination pathwayDNA moleculesProteinInvasionMeiosisPreserving genome integrity in human cells via DNA double-strand break repair
Jensen RB, Rothenberg E. Preserving genome integrity in human cells via DNA double-strand break repair. Molecular Biology Of The Cell 2020, 31: 859-865. PMID: 32286930, PMCID: PMC7185975, DOI: 10.1091/mbc.e18-10-0668.Peer-Reviewed Original ResearchConceptsGenome integrityHuman cellsHuman diseasesRepair pathwaysDNA DSB repair pathwaysDNA double-strand break repairDNA double-strand break repair pathwayDouble-strand break repair pathwayDouble-strand break repairDSB repair pathwaysCell cycle checkpointsBreak repair pathwayFull tumorigenic potentialDNA repair failureChromatin dynamicsGenome stabilityNuclear architectureCellular signalingDNA replicationBreak repairCellular stressCycle checkpointsDNA repairCellular activitiesHomologous recombination-deficient tumorsBRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing
Zhao W, Steinfeld JB, Liang F, Chen X, Maranon DG, Jian Ma C, Kwon Y, Rao T, Wang W, Sheng C, Song X, Deng Y, Jimenez-Sainz J, Lu L, Jensen RB, Xiong Y, Kupfer GM, Wiese C, Greene EC, Sung P. BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing. Nature 2017, 550: 360-365. PMID: 28976962, PMCID: PMC5800781, DOI: 10.1038/nature24060.Peer-Reviewed Original ResearchAmino Acid SequenceBase PairingBRCA1 ProteinBRCA2 ProteinChromosome PairingFanconi Anemia Complementation Group N ProteinGenes, BRCA1Genes, BRCA2HumansMultiprotein ComplexesMutationProtein BindingRad51 RecombinaseRecombinational DNA RepairSequence Homology, Nucleic AcidTemplates, GeneticTumor Suppressor ProteinsUbiquitin-Protein LigasesEnhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP
Daley JM, Jimenez-Sainz J, Wang W, Miller AS, Xue X, Nguyen KA, Jensen RB, Sung P. Enhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP. Cell Reports 2017, 21: 324-332. PMID: 29020620, PMCID: PMC5689478, DOI: 10.1016/j.celrep.2017.09.048.Peer-Reviewed Original ResearchA 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 penetrationThe 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 agentsLevelsVariantsDistinct binding of BRCA2 BRC repeats to RAD51 generates differential DNA damage sensitivity
Chatterjee G, Jimenez-Sainz J, Presti T, Nguyen T, Jensen RB. Distinct binding of BRCA2 BRC repeats to RAD51 generates differential DNA damage sensitivity. Nucleic Acids Research 2016, 44: 5256-5270. PMID: 27084934, PMCID: PMC4914107, DOI: 10.1093/nar/gkw242.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksDomain of BRCA2Homology-directed repairDouble-strand breaksBRC repeatsDNA damageDNA damage sensitivityPatient-derived mutationsRegulation of RAD51Cellular DNA damageComplementation functionRepair complexRAD51 bindingRad51 filamentsDNA substratesHomologous recombinationFaceted proteinProper regulationStrand pairingRAD51Damage sensitivityCellular propertiesRepeatsCellular featuresRepeat unitsPromotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry
Zhao W, Vaithiyalingam S, San Filippo J, Maranon DG, Jimenez-Sainz J, Fontenay GV, Kwon Y, Leung SG, Lu L, Jensen RB, Chazin WJ, Wiese C, Sung P. Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry. Molecular Cell 2015, 59: 176-187. PMID: 26145171, PMCID: PMC4506714, DOI: 10.1016/j.molcel.2015.05.032.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SubstitutionBRCA2 ProteinBreast NeoplasmsCell LineFemaleHeLa CellsHomologous RecombinationHumansModels, BiologicalMolecular MimicryMutagenesis, Site-DirectedNuclear Magnetic Resonance, BiomolecularProteasome Endopeptidase ComplexProtein SubunitsRad51 RecombinaseRecombinant ProteinsReplication Protein AConceptsReplication protein AHomologous recombinationAffinity of RPAReplication fork repairTumor suppressor BRCA2DNA mimicryGenome maintenanceFork repairMediator complexRAD51 recombinaseAcidic domainDNA breaksBiological processesTumor suppressionDSS1Vivo analysisProtein ADNA mimicsSsDNARecombinationBRCA2ComplexesRecombinaseDNAMutationsPurification of Recombinant 2XMBP Tagged Human Proteins from Human Cells
Jensen R. Purification of Recombinant 2XMBP Tagged Human Proteins from Human Cells. Methods In Molecular Biology 2014, 1176: 209-217. PMID: 25030930, DOI: 10.1007/978-1-4939-0992-6_17.Peer-Reviewed Original ResearchBRCA2: one small step for DNA repair, one giant protein purified.
Jensen RB. BRCA2: one small step for DNA repair, one giant protein purified. The Yale Journal Of Biology And Medicine 2013, 86: 479-89. PMID: 24348212, PMCID: PMC3848102.Peer-Reviewed Original ResearchConceptsHomologous recombinationDNA repairDNA double-strand break repairActivity of Rad51Double-strand break repairDNA double-strand breaksReplication protein A.Homologous DNA sequencesDouble-strand breaksCurrent biochemical dataHigh-fidelity repairRole of BRCA2Faithful repairRad51 proteinNucleoprotein filamentBreak repairSingle-strand DNADNA sequencesGenomic instabilityDNA breaksGiant proteinRAD51Gene BRCA2BRCA2 proteinCentral playerBRCA2 is epistatic to the RAD51 paralogs in response to DNA damage
Jensen RB, Ozes A, Kim T, Estep A, Kowalczykowski SC. BRCA2 is epistatic to the RAD51 paralogs in response to DNA damage. DNA Repair 2013, 12: 306-311. PMID: 23384538, PMCID: PMC3602134, DOI: 10.1016/j.dnarep.2012.12.007.Peer-Reviewed Original ResearchConceptsRAD51 paralogsHomologous recombinationDNA double-strand breaksDNA damage responseDNA DSB repairDonor DNA moleculesDouble-strand breaksHigh-fidelity repairLoss of BRCA2SiRNA-mediated knockdownHuman BRCA2 proteinCell cycle arrestGenetic interactionsSister chromatidsDamage responseDSB repairMammalian cellsParalogsRegulated eventDNA breaksEnzymatic functionMechanistic functionBRCA2 proteinCentral playerHuman cellsPurified human BRCA2 stimulates RAD51-mediated recombination
Jensen RB, Carreira A, Kowalczykowski SC. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature 2010, 467: 678-683. PMID: 20729832, PMCID: PMC2952063, DOI: 10.1038/nature09399.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsApoptosis Regulatory ProteinsBRCA2 ProteinCell Cycle ProteinsCell LineChromosomal InstabilityDNADNA RepairDNA, Single-StrandedDNA-Binding ProteinsHumansMutationProtein BindingRad51 RecombinaseRecombination, GeneticReplication Protein ASequence Homology, Nucleic AcidSubstrate SpecificityConceptsHuman BRCA2Assembly of RAD51Rad51-ssDNA filamentRecombinational DNA repairDNA repair processesBreast cancer susceptibility genesRepair processReplication proteinsCancer susceptibility genesSsDNA annealingBind RAD51Homologous recombinationDNA repairMolecular basisATP hydrolysisRAD51Large proteinsChromosomal instabilitySusceptibility genesMechanistic insightsKey mediatorProteinDNAMutationsBRCA2Cell-interdependent cisplatin killing by Ku/DNA-dependent protein kinase signaling transduced through gap junctions
Jensen R, Glazer PM. Cell-interdependent cisplatin killing by Ku/DNA-dependent protein kinase signaling transduced through gap junctions. Proceedings Of The National Academy Of Sciences Of The United States Of America 2004, 101: 6134-6139. PMID: 15069205, PMCID: PMC395935, DOI: 10.1073/pnas.0400051101.Peer-Reviewed Original ResearchConceptsDNA-dependent protein kinase (DNA-PK) complexDNA-dependent protein kinase activityDNA-dependent protein kinaseProtein kinase complexProtein kinase activityCell-autonomous mannerGap junctionsBlock transcriptionKinase complexKinase functionProtein kinaseDeath signalsDNA repairCell communicationKinase activityRecipient cellsCellular componentsGap junction expressionHuman cancersNeighboring cellsDirect cellCell killingMechanism of actionCellsJunction expression
2024
PARG inhibition induces nuclear aggregation of PARylated PARP1
Paradkar S, Purcell J, Cui A, Friedman S, Noronha K, Murray M, Sundaram R, Bindra R, Jensen R. PARG inhibition induces nuclear aggregation of PARylated PARP1. Structure 2024, 32: 2083-2093.e5. PMID: 39406247, DOI: 10.1016/j.str.2024.09.006.Peer-Reviewed Original Research