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 ResearchMeSH KeywordsBRCA2 ProteinDNA RepairDNA, Single-StrandedMutation, MissenseNucleoproteinsRad51 RecombinaseConceptsHomology-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 predisposeBRC2Imprecise 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 variantsPatientsDNA 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 moleculesProteinInvasionMeiosisBRCA1–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 LigasesThe 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 ResearchMeSH KeywordsAmino Acid MotifsBRCA2 ProteinDNA DamageProtein BindingProtein Interaction Domains and MotifsRad51 RecombinaseConceptsDNA 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 mimicsSsDNARecombinationBRCA2ComplexesRecombinaseDNAMutationsBRCA2: 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 mediatorProteinDNAMutationsBRCA2
2024
Dormant origin firing promotes head-on transcription-replication conflicts at transcription termination sites in response to BRCA2 deficiency
Goehring L, Keegan S, Lahiri S, Xia W, Kong M, Jimenez-Sainz J, Gupta D, Drapkin R, Jensen R, Smith D, Rothenberg E, Fenyö D, Huang T. Dormant origin firing promotes head-on transcription-replication conflicts at transcription termination sites in response to BRCA2 deficiency. Nature Communications 2024, 15: 4716. PMID: 38830843, PMCID: PMC11148086, DOI: 10.1038/s41467-024-48286-1.Peer-Reviewed Original ResearchConceptsTranscription termination sitesTranscription-replication conflictsDormant originsReplication stressElongating RNA polymerase IITermination sitesResponse to replication stressRNA polymerase IIR-loop formationTumor suppressor proteinPolymerase IIR-loopsLong genesRNase H2Transcription initiationOK-seqGenomic sitesSuppressor proteinCellular genomeBRCA2 deficiencyOrigin firingSuper-resolution microscopyGenomic instabilityDormant origin firingTranscription
2023
BRCA2 chaperones RAD51 to single molecules of RPA-coated ssDNA
Bell J, Dombrowski C, Plank J, Jensen R, Kowalczykowski S. BRCA2 chaperones RAD51 to single molecules of RPA-coated ssDNA. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2221971120. PMID: 36976771, PMCID: PMC10083600, DOI: 10.1073/pnas.2221971120.Peer-Reviewed Original Research
2019
The Post-Synaptic Function of Brca2
Wang CX, Jimenez-Sainz J, Jensen RB, Mazin AV. The Post-Synaptic Function of Brca2. Scientific Reports 2019, 9: 4554. PMID: 30872704, PMCID: PMC6418147, DOI: 10.1038/s41598-019-41054-y.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksHomologous recombinationMammalian cellsRegulation of HRDisplacement loop (D-loop) structureDouble-strand breaksPresynaptic nucleoprotein filamentHigh-fidelity processRAD51 activityGenetic diversityNucleoprotein filamentDSB repairHomologous dsDNAD-loopPost-synaptic functionRAD51Mechanistic underpinningsBiologic functionsUnexpected activityLoop structureBRCA2SsDNAFilamentsCellsDiversity