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 predisposeBRC2Polymerase 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 defectsPreserving 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 tumorsA 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 penetrationBRCA2: 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 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