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 predisposeBRC2Human 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 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 agentsLevelsVariantsBRCA2: 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 playerPurified 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
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
2003
Decreased Expression of the DNA Mismatch Repair Gene Mlh1 under Hypoxic Stress in Mammalian Cells
Mihaylova VT, Bindra RS, Yuan J, Campisi D, Narayanan L, Jensen R, Giordano F, Johnson RS, Rockwell S, Glazer PM. Decreased Expression of the DNA Mismatch Repair Gene Mlh1 under Hypoxic Stress in Mammalian Cells. Molecular And Cellular Biology 2003, 23: 3265-3273. PMID: 12697826, PMCID: PMC153206, DOI: 10.1128/mcb.23.9.3265-3273.2003.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdenosine TriphosphatasesAnimalsBase Pair MismatchBeta-GalactosidaseCarrier ProteinsCell HypoxiaCells, CulturedDeferoxamineDinucleotide RepeatsDNA RepairDNA Repair EnzymesDNA-Binding ProteinsEnzyme InhibitorsFibroblastsGenes, ReporterHeLa CellsHumansHydroxamic AcidsHypoxia-Inducible Factor 1, alpha SubunitIron Chelating AgentsMethylationMiceMice, TransgenicMismatch Repair Endonuclease PMS2MutL Protein Homolog 1MutS Homolog 2 ProteinNeoplasm ProteinsNuclear ProteinsProto-Oncogene ProteinsRNA, MessengerTranscription FactorsConceptsGenetic instabilityMammalian cellsDNA mismatch repair genes MLH1Chromosomal reporter geneHistone deacetylase inhibitor trichostatin AStationary-phase mutagenesisDeacetylase inhibitor trichostatin AInhibitor trichostatin AMismatch repair genes MLH1Treatment of cellsHistone deacetylationStress signalsKey MMR proteinsReporter geneGenes MLH1Gene expressionLow oxygen tensionPMS2 levelsMMR gene expressionTrichostatin AMLH1 mRNAPotential new pathwaysDinucleotide repeatsHeterodimer partnerHypoxia-induced reduction