2019
Intra-Vκ Cluster Recombination Shapes the Ig Kappa Locus Repertoire
Shinoda K, Maman Y, Canela A, Schatz DG, Livak F, Nussenzweig A. Intra-Vκ Cluster Recombination Shapes the Ig Kappa Locus Repertoire. Cell Reports 2019, 29: 4471-4481.e6. PMID: 31875554, PMCID: PMC8214342, DOI: 10.1016/j.celrep.2019.11.088.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksRecombination signal sequencesVκ gene segmentsGene segmentsDouble-strand breaksVariable gene segmentsRAG proteinsSignal sequenceV-J rearrangementRecombination eventsSpacer regionVκ-JκRecombinationLevels of breakageComplete absenceProteinLarge fractionDeletionJκSequence
2017
Immature Lymphocytes Inhibit Rag1 and Rag2 Transcription and V(D)J Recombination in Response to DNA Double-Strand Breaks
Fisher MR, Rivera-Reyes A, Bloch NB, Schatz DG, Bassing CH. Immature Lymphocytes Inhibit Rag1 and Rag2 Transcription and V(D)J Recombination in Response to DNA Double-Strand Breaks. The Journal Of Immunology 2017, 198: 2943-2956. PMID: 28213501, PMCID: PMC5360515, DOI: 10.4049/jimmunol.1601639.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksDNA damage responseRAG1/RAG2Double-strand breaksRAG DNA double-strand breaksMultiple genomic locationsTranscription of genesNF-κB transcription factorsDSB responseGenomic integrityGenomic locationATM kinaseTranscriptional repressionRAG cleavageCellular functionsDamage responseLocus recombinationMammalian cellsRAG1 proteinTranscription factorsModulator proteinRAG expressionAtaxia telangiectasiaTranscriptional inhibitionDevelopmental stages
2015
Spatio-temporal regulation of RAG2 following genotoxic stress
Rodgers W, Byrum JN, Sapkota H, Rahman NS, Cail RC, Zhao S, Schatz DG, Rodgers KK. Spatio-temporal regulation of RAG2 following genotoxic stress. DNA Repair 2015, 27: 19-27. PMID: 25625798, PMCID: PMC4336829, DOI: 10.1016/j.dnarep.2014.12.008.Peer-Reviewed Original ResearchMeSH KeywordsActive Transport, Cell NucleusAtaxia Telangiectasia Mutated ProteinsCell NucleusCells, CulturedCentrosomeDNADNA Breaks, Double-StrandedDNA RepairDNA-Binding ProteinsGene Knockdown TechniquesHumansMicroscopy, FluorescenceMutationNuclear ProteinsPrecursor Cells, B-LymphoidRadiation, IonizingSubcellular FractionsVDJ RecombinasesConceptsDNA double-strand breaksGenotoxic stressorsCellular responsesFormation of DSBsLymphocyte antigen receptor genesDNA DSBsSpatio-temporal regulationInhibition of ATMDNA damaging agentsSubcellular fractionation approachDouble-strand breaksAntigen receptor genesNuclear Rag2Genotoxic stressRAG complexDNA repairIncorrect repairDamaging agentsStrand breaksNovel mechanismRAG2Receptor geneCentrosomesFractionation approachSubstantial enrichment
2013
The Ataxia Telangiectasia mutated kinase controls Igκ allelic exclusion by inhibiting secondary Vκ-to-Jκ rearrangements
Steinel NC, Lee BS, Tubbs AT, Bednarski JJ, Schulte E, Yang-Iott KS, Schatz DG, Sleckman BP, Bassing CH. The Ataxia Telangiectasia mutated kinase controls Igκ allelic exclusion by inhibiting secondary Vκ-to-Jκ rearrangements. Journal Of Experimental Medicine 2013, 210: 233-239. PMID: 23382544, PMCID: PMC3570110, DOI: 10.1084/jem.20121605.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAllelesAnimalsAtaxia Telangiectasia Mutated ProteinsB-LymphocytesBase SequenceCell Cycle ProteinsDNA Breaks, Double-StrandedDNA-Binding ProteinsGene Rearrangement, B-Lymphocyte, Light ChainHistonesHomeodomain ProteinsImmunoglobulin kappa-ChainsIntracellular Signaling Peptides and ProteinsMiceMice, 129 StrainMice, KnockoutModels, BiologicalProtein Serine-Threonine KinasesRNA, MessengerSignal TransductionTumor Suppressor ProteinsConceptsDNA double-strand breaksRAG DNA double-strand breaksAllelic exclusionIgκ rearrangementAtaxia telangiectasiaProtein kinase kinaseAntigen receptor chainsDouble-strand breaksHistone H2AX phosphorylationFeedback inhibitionATM kinaseIgκ recombinationKinase kinaseDNA-PKConcomitant repressionH2AX phosphorylationRAG endonucleaseReceptor chainsMDC1H2AXKinaseAllelesRecombinationRearrangementTelangiectasia
2012
A Dual Interaction between the DNA Damage Response Protein MDC1 and the RAG1 Subunit of the V(D)J Recombinase*
Coster G, Gold A, Chen D, Schatz DG, Goldberg M. A Dual Interaction between the DNA Damage Response Protein MDC1 and the RAG1 Subunit of the V(D)J Recombinase*. Journal Of Biological Chemistry 2012, 287: 36488-36498. PMID: 22942284, PMCID: PMC3476314, DOI: 10.1074/jbc.m112.402487.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAmino Acid MotifsBRCA1 ProteinCell Cycle ProteinsCell Line, TumorHistonesHomeodomain ProteinsHumansModels, BiologicalNuclear ProteinsPeptide MappingPhosphorylationProtein Structure, TertiaryRepetitive Sequences, Amino AcidTrans-ActivatorsVDJ RecombinasesConceptsDNA double-strand breaksDNA damage responseTandem BRCA1 C-terminal (BRCT) domainsC-terminusSpecific DNA double-strand breaksBRCA1 C-terminal domainC-terminal domainThreonine-rich repeatsDouble-strand breaksRAG1 subunitRAG recombinaseRAG2 proteinsDDR proteinsDamage responseRegulatory signalsBinding interfaceBreak siteHistone H2AXRAG activityRich repeatsNon-core regionsMDC1RAG1PhosphorylationSubsequent signal amplificationDendritic cell–mediated activation-induced cytidine deaminase (AID)–dependent induction of genomic instability in human myeloma
Koduru S, Wong E, Strowig T, Sundaram R, Zhang L, Strout MP, Flavell RA, Schatz DG, Dhodapkar KM, Dhodapkar MV. Dendritic cell–mediated activation-induced cytidine deaminase (AID)–dependent induction of genomic instability in human myeloma. Blood 2012, 119: 2302-2309. PMID: 22234692, PMCID: PMC3311257, DOI: 10.1182/blood-2011-08-376236.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternCell Line, TumorCell SurvivalCells, CulturedCoculture TechniquesCytidine DeaminaseDendritic CellsDNA Breaks, Double-StrandedFemaleGene Expression Regulation, EnzymologicGene Expression Regulation, NeoplasticGenomic InstabilityHumansInterleukin Receptor Common gamma SubunitMiceMice, Inbred NODMice, KnockoutMice, SCIDMultiple MyelomaNF-kappa BRANK LigandReverse Transcriptase Polymerase Chain ReactionTransplantation, HeterologousTumor Cells, CulturedConceptsInduction of AIDMultiple myelomaTumor microenvironmentTumor cellsReceptor activatorActivation-induced cytidine deaminaseDendritic cell infiltrationCapacity of DCPrimary MM cellsNF-κB/receptor activatorGenetics of tumorsGrowth of tumorsGenomic damageMyeloma cell linesRANKL inhibitionPlasmacytoid DCsIndolent behaviorCell infiltrationMM cellsHuman myelomaCytidine deaminaseMyelomaDNA double-strand breaksGenomic instabilityCell lines
2009
Leaky severe combined immunodeficiency and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation
Giblin W, Chatterji M, Westfield G, Masud T, Theisen B, Cheng HL, DeVido J, Alt FW, Ferguson DO, Schatz DG, Sekiguchi J. Leaky severe combined immunodeficiency and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation. Blood 2009, 113: 2965-2975. PMID: 19126872, PMCID: PMC2662642, DOI: 10.1182/blood-2008-07-165167.Peer-Reviewed Original ResearchConceptsDouble-strand breaksHypomorphic RAG1 mutationsImmune system dysfunctionDNA rearrangementsKnockin mouse modelP53 mutant backgroundAberrant DNA rearrangementsDNA double-strand breaksPremature immunosenescenceDNA end processingSystem dysfunctionRecombination signal sequencesMouse modelRAG1 mutationsImmune systemMice exhibitAntigen receptor genesThymic lymphomasTumor developmentVivo evidenceMutant backgroundLymphocyte developmentSignal sequenceReceptor geneHypomorphic mutations
2004
Staggered AID‐dependent DNA double strand breaks are the predominant DNA lesions targeted to Sµ in Ig class switch recombination
Rush JS, Fugmann SD, Schatz DG. Staggered AID‐dependent DNA double strand breaks are the predominant DNA lesions targeted to Sµ in Ig class switch recombination. International Immunology 2004, 16: 549-557. PMID: 15039385, DOI: 10.1093/intimm/dxh057.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalBlotting, SouthernB-LymphocytesCell DivisionCytidine DeaminaseDeoxyribonucleases, Type II Site-SpecificDNADNA DamageDNA PrimersFlow CytometryGene ExpressionImmunoglobulin Class SwitchingImmunoglobulin DImmunoglobulin GImmunoglobulin Switch RegionInterleukin-4LipopolysaccharidesMiceMice, Inbred C57BLMice, KnockoutPlasmidsPolymerase Chain ReactionRecombination, GeneticConceptsClass switch recombinationDNA double-strand breaksPredominant DNA lesionsDouble-strand breaksActivation-induced cytidine deaminaseDNA lesionsSwitch recombinationAID-dependent DNA double-strand breaksStrand breaksIg class switch recombinationLigation-mediated PCRS mu regionCellular regulationKinetics of inductionMolecular detailsMurine B cellsDNA DSBsStaggered breaksCytidine deaminaseDSBsMu regionMinor speciesB cellsS muEffector properties
2000
Cell-cycle-regulated DNA double-strand breaks in somatic hypermutation of immunoglobulin genes
Papavasiliou F, Schatz D. Cell-cycle-regulated DNA double-strand breaks in somatic hypermutation of immunoglobulin genes. Nature 2000, 408: 216-221. PMID: 11089977, DOI: 10.1038/35041599.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksDouble-strand breaksSomatic hypermutationRepair of DSBsVariable region promotersImmunoglobulin variable region genesDNA replicationHomologous recombinationHeterologous promoterSpecific residuesVariable genesNearby mutationsRegion promoterVariable region genesImmunoglobulin genesHeterologous sequencesChromosomal translocationsPoint mutationsGenesRegion genesMutationsHypermutationTranscriptionPromoterB-cell tumors