2020
Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID
Kuhny M, Forbes LR, Çakan E, Vega-Loza A, Kostiuk V, Dinesh RK, Glauzy S, Stray-Pedersen A, Pezzi AE, Hanson IC, Vargas-Hernandez A, Xu ML, Akdemir Z, Jhangiani SN, Muzny DM, Gibbs RA, Lupski JR, Chinn IK, Schatz DG, Orange JS, Meffre E. Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID. Journal Of Clinical Investigation 2020, 130: 4411-4422. PMID: 32484799, PMCID: PMC7410074, DOI: 10.1172/jci131297.Peer-Reviewed Original ResearchConceptsB cellsActivation-induced cytidine deaminaseHealthy donor counterpartsIsotype-switched B cellsCommon variable immunodeficiencyMemory B cellsSomatic hypermutationAutoimmune cytopeniasDecreased incidenceVariable immunodeficiencyB cell linesUnderlying molecular defectsNuclear AIDPatient's EBVRamos B cellsPatientsProtein 1Cell linesMolecular defectsCellsCytidine deaminaseMutations
2016
Bcl6 Is Required for Somatic Hypermutation and Gene Conversion in Chicken DT40 Cells
Williams AM, Maman Y, Alinikula J, Schatz DG. Bcl6 Is Required for Somatic Hypermutation and Gene Conversion in Chicken DT40 Cells. PLOS ONE 2016, 11: e0149146. PMID: 26900682, PMCID: PMC4762950, DOI: 10.1371/journal.pone.0149146.Peer-Reviewed Original ResearchConceptsDT40 cellsGene conversionTarget genesClass switch recombinationGene bodiesSomatic hypermutationB cell gene expression programChicken DT40 B cellsBCL6 functionCell gene expression programChicken DT40 cellsDT40 B cellsGene expression programsRNA polymerase IIDeficient DT40 cellsTranscription start siteExpression of AIDAbsence of Bcl6High-level expressionB cellsExpression programsPolymerase IIPol IIStart siteTranscriptional features
2015
Recruitment of RAG1 and RAG2 to Chromatinized DNA during V(D)J Recombination
Shetty K, Schatz DG. Recruitment of RAG1 and RAG2 to Chromatinized DNA during V(D)J Recombination. Molecular And Cellular Biology 2015, 35: 3701-3713. PMID: 26303526, PMCID: PMC4589606, DOI: 10.1128/mcb.00219-15.Peer-Reviewed Original ResearchConceptsConserved heptamerRAG2 proteinsChromatin immunoprecipitationNonamer elementsRecombination substratesSignal sequenceNonamer sequencesMutant formsCryptic RSSsRAG1DNA cleavageGene segmentsChromatinCell linesRAG2ProteinRecruitmentRecombinationSequenceMajor roleMutagenesisImmunoprecipitationRepeatsRSSsRAGRAG Represents a Widespread Threat to the Lymphocyte Genome
Teng G, Maman Y, Resch W, Kim M, Yamane A, Qian J, Kieffer-Kwon KR, Mandal M, Ji Y, Meffre E, Clark MR, Cowell LG, Casellas R, Schatz DG. RAG Represents a Widespread Threat to the Lymphocyte Genome. Cell 2015, 162: 751-765. PMID: 26234156, PMCID: PMC4537821, DOI: 10.1016/j.cell.2015.07.009.Peer-Reviewed Original ResearchConceptsRecombination signalsStrong recombination signalGenome stabilityHuman genomeActive promotersGenomeDNA damageChromosomal translocationsCleavage siteWidespread threatRAG1Lymphocyte genomeEvolutionary struggleRecombinationRAGChromatinPromoterEndonucleaseSitesRAG2TranslocationAbundanceDepletionEnhancerHeptamer
2014
Targeting Of Somatic Hypermutation By immunoglobulin Enhancer And Enhancer-Like Sequences
Buerstedde JM, Alinikula J, Arakawa H, McDonald JJ, Schatz DG. Targeting Of Somatic Hypermutation By immunoglobulin Enhancer And Enhancer-Like Sequences. PLOS Biology 2014, 12: e1001831. PMID: 24691034, PMCID: PMC3972084, DOI: 10.1371/journal.pbio.1001831.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodiesBinding SitesB-LymphocytesCell LineChickensCytidine DeaminaseE-Box ElementsEnhancer Elements, GeneticGene Knockout TechniquesGreen Fluorescent ProteinsHumansImmunoglobulin kappa-ChainsImmunoglobulin lambda-ChainsLymphocyte ActivationMEF2 Transcription FactorsMiceMutationNF-kappa BSequence AlignmentSomatic Hypermutation, ImmunoglobulinTranscription, GeneticUracil-DNA GlycosidaseConceptsSomatic hypermutationIg enhancersNovel regulatory functionStimulation of transcriptionEnhancer-like elementCytidine deaminase proteinEnhancer-like sequenceActivation-induced cytidine deaminase proteinGene specificityTranscriptional roleHeavy chain intron enhancerTranscription unitGenetic diversityEts familyE-boxChicken cellsRegulatory functionsIntron enhancerFull activationImmunoglobulin genesTarget sequenceImmunoglobulin enhancerPoint mutationsEnhancerTranscriptionInduction of homologous recombination between sequence repeats by the activation induced cytidine deaminase (AID) protein
Buerstedde JM, Lowndes N, Schatz DG. Induction of homologous recombination between sequence repeats by the activation induced cytidine deaminase (AID) protein. ELife 2014, 3: e03110. PMID: 25006166, PMCID: PMC4080448, DOI: 10.7554/elife.03110.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceB-LymphocytesCell LineChickensCrossing Over, GeneticCytidine DeaminaseGene ConversionGenes, ReporterGreen Fluorescent ProteinsHomologous RecombinationHumansImmunoglobulin Switch RegionLuminescent ProteinsMiceModels, GeneticMolecular Sequence DataNucleic Acid HeteroduplexesRecombinational DNA RepairRepetitive Sequences, Nucleic AcidSequence DeletionSequence Homology, Nucleic AcidSomatic Hypermutation, ImmunoglobulinConceptsHomologous recombinationCytidine deaminase proteinSequence repeatsCytidine deaminationDNA end resectionHundreds of basesAnalysis of recombinantsVertebrate cellsGene conversionRepeat recombinationEnd resectionHolliday junctionsHomologous sequencesSequence homologyReporter transgeneStrand invasionIntergenic deletionRecombinogenic activityImmunoglobulin lociRepeatsSomatic hypermutationHeteroduplex formationRecombinationProteinDeamination
2012
Localized epigenetic changes induced by DH recombination restricts recombinase to DJH junctions
Subrahmanyam R, Du H, Ivanova I, Chakraborty T, Ji Y, Zhang Y, Alt FW, Schatz DG, Sen R. Localized epigenetic changes induced by DH recombination restricts recombinase to DJH junctions. Nature Immunology 2012, 13: 1205-1212. PMID: 23104096, PMCID: PMC3685187, DOI: 10.1038/ni.2447.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesCell LineChromatinEpigenesis, GeneticGene Rearrangement, B-Lymphocyte, Heavy ChainGenes, Immunoglobulin Heavy ChainHistonesImmunoglobulin Heavy ChainsImmunoglobulin Joining RegionImmunoglobulin Variable RegionMicePrecursor Cells, B-LymphoidRecombinasesRecombination, Genetic
2007
Role of Activation-Induced Deaminase Protein Kinase A Phosphorylation Sites in Ig Gene Conversion and Somatic Hypermutation
Chatterji M, Unniraman S, McBride KM, Schatz DG. Role of Activation-Induced Deaminase Protein Kinase A Phosphorylation Sites in Ig Gene Conversion and Somatic Hypermutation. The Journal Of Immunology 2007, 179: 5274-5280. PMID: 17911613, DOI: 10.4049/jimmunol.179.8.5274.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAmino Acid SubstitutionAnimalsAvian ProteinsCell LineChickensCyclic AMP-Dependent Protein KinasesCytidine DeaminaseEnzyme ActivationGene ConversionGenes, ImmunoglobulinHumansMiceMolecular Sequence DataPhosphorylationSerineSomatic Hypermutation, ImmunoglobulinZebrafish ProteinsConceptsReplication protein AActivation-induced deaminaseProtein kinase AClass switch recombinationGene conversionDT40 cellsPhosphorylation sitesSomatic hypermutationProtein kinase A (PKA) phosphorylation siteChicken DT40 cellsIg gene conversionEfficient gene conversionConsensus target siteIg gene diversificationGene diversificationSerine 38Cytosine residuesKinase ASwitch recombinationIg genesResidue interferesFish proteinTarget siteProtein AS38The Beyond 12/23 Restriction Is Imposed at the Nicking and Pairing Steps of DNA Cleavage during V(D)J Recombination
Drejer-Teel AH, Fugmann SD, Schatz DG. The Beyond 12/23 Restriction Is Imposed at the Nicking and Pairing Steps of DNA Cleavage during V(D)J Recombination. Molecular And Cellular Biology 2007, 27: 6288-6299. PMID: 17636023, PMCID: PMC2099602, DOI: 10.1128/mcb.00835-07.Peer-Reviewed Original ResearchConceptsRecombination signal sequencesDNA cleavageGene segmentsDNA cleavage stepRecombination-activating gene 1Dbeta gene segmentVariable region exonsJbeta gene segmentsRAG proteinsDNA elementsSignal sequenceDirect VbetaRegion exonsGene 1Oligonucleotide substratesLocus sequenceDistinct combinationsProteinRecombinationCleavageNickingCleavage stepSequenceDifferent stepsExonsActivation-induced Cytidine Deaminase-mediated Sequence Diversification Is Transiently Targeted to Newly Integrated DNA Substrates*
Yang SY, Fugmann SD, Gramlich HS, Schatz DG. Activation-induced Cytidine Deaminase-mediated Sequence Diversification Is Transiently Targeted to Newly Integrated DNA Substrates*. Journal Of Biological Chemistry 2007, 282: 25308-25313. PMID: 17613522, DOI: 10.1074/jbc.m704231200.Peer-Reviewed Original ResearchConceptsActivation-induced cytidine deaminaseChicken B cell line DT40B cell line DT40Cytidine deaminaseNon-Ig lociNon-Ig genesSequence diversificationDNA substratesTranscription cassetteMutation targetsCassetteMolecular characteristicsMolecular featuresDeaminaseDT40TranscriptionGenesLociDNADiversificationMutabilityTargetingIgTarget
2006
Mobilization of RAG-Generated Signal Ends by Transposition and Insertion In Vivo
Chatterji M, Tsai CL, Schatz DG. Mobilization of RAG-Generated Signal Ends by Transposition and Insertion In Vivo. Molecular And Cellular Biology 2006, 26: 1558-1568. PMID: 16449665, PMCID: PMC1367191, DOI: 10.1128/mcb.26.4.1558-1568.2006.Peer-Reviewed Original ResearchConceptsRAG proteinsVertebrate cellsTransposition eventsEnd fragmentsFull-length RAG2Embryonic kidney cell lineHuman embryonic kidney cell lineTarget site duplicationsGenome instabilityHuman genomeSignal endsKidney cell lineGenomic instabilityTranslocation eventsSite duplicationsChromosomal translocationsDNA cleavageComplex rearrangementsChromosome deletionsEssential roleProteinCell linesEpisomesDeletionAssays
2005
Biochemistry of V(D)J Recombination
Schatz DG, Spanopoulou E. Biochemistry of V(D)J Recombination. Current Topics In Microbiology And Immunology 2005, 290: 49-85. PMID: 16480039, DOI: 10.1007/3-540-26363-2_4.Peer-Reviewed Original Research
2004
Pax5-Deficient Mice Exhibit Early Onset Osteopenia with Increased Osteoclast Progenitors
Horowitz MC, Xi Y, Pflugh DL, Hesslein DG, Schatz DG, Lorenzo JA, Bothwell AL. Pax5-Deficient Mice Exhibit Early Onset Osteopenia with Increased Osteoclast Progenitors. The Journal Of Immunology 2004, 173: 6583-6591. PMID: 15557148, DOI: 10.4049/jimmunol.173.11.6583.Peer-Reviewed Original ResearchConceptsNumber of osteoclastsSpleen cellsB cellsOsteoclast developmentB cell-deficient miceCell-deficient miceControl spleen cellsB lymphocyte lineage cellsBone marrow cellsB-cell lineagePro-B cell stageMonocyte phenotypeBone massOsteoclast precursorsMice exhibitOsteoclast progenitorsMarrow cellsGrowth factorMiceOsteoclastsLineage cellsOsteopeniaCell lineagesCellsAdherent cellsMutational Analysis of Terminal Deoxynucleotidyltransferase- Mediated N-Nucleotide Addition in V(D)J Recombination
Repasky JA, Corbett E, Boboila C, Schatz DG. Mutational Analysis of Terminal Deoxynucleotidyltransferase- Mediated N-Nucleotide Addition in V(D)J Recombination. The Journal Of Immunology 2004, 172: 5478-5488. PMID: 15100289, DOI: 10.4049/jimmunol.172.9.5478.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibody DiversityCell LineCHO CellsCricetinaeDNA Mutational AnalysisDNA NucleotidylexotransferaseDNA-Binding ProteinsGene RearrangementHomeodomain ProteinsHumansImmunoglobulin Joining RegionImmunoglobulin Variable RegionIsoenzymesMiceNuclear ProteinsNucleotidesOpen Reading FramesPlasmidsRecombination, GeneticSignal TransductionSubstrate SpecificityTemplates, GeneticConceptsNucleotide additionEntire C-terminal regionAg receptor genesProtein-DNA interactionsC-terminal domainStructure-function analysisC-terminal regionN-terminal portionIndividual structural motifsUnique DNA polymeraseBRCT domainHelix domainTdT proteinCatalytic regionDeletional analysisMutational analysisLong isoformNontemplated (N) nucleotidesNucleotide deletionDNA polymeraseDiverse repertoireReceptor geneStructural motifsNonlymphoid cellsCritical role
2003
DNA mismatches and GC‐rich motifs target transposition by the RAG1/RAG2 transposase
Tsai C, Chatterji M, Schatz DG. DNA mismatches and GC‐rich motifs target transposition by the RAG1/RAG2 transposase. Nucleic Acids Research 2003, 31: 6180-6190. PMID: 14576304, PMCID: PMC275461, DOI: 10.1093/nar/gkg819.Peer-Reviewed Original ResearchA Functional Analysis of the Spacer of V(D)J Recombination Signal Sequences
Lee AI, Fugmann SD, Cowell LG, Ptaszek LM, Kelsoe G, Schatz DG. A Functional Analysis of the Spacer of V(D)J Recombination Signal Sequences. PLOS Biology 2003, 1: e1. PMID: 14551903, PMCID: PMC212687, DOI: 10.1371/journal.pbio.0000001.Peer-Reviewed Original ResearchConceptsRecombination signal sequencesSignal sequenceGene segmentsProtein-DNA interactionsLevel of recombinationDegree of conservationParticular functional importanceJ gene segmentsAntigen receptor genesSpacer variantsRAG proteinsRecombination machineryRSS activityInactive pseudogeneRSS functionSpacer sequencesFunctional analysisInteraction surfaceFunctional importanceLymphocyte developmentNumerous complex interactionsBiochemical assaysDistinct cooperationReceptor geneHeptamerDefective DNA Repair and Increased Genomic Instability in Artemis-deficient Murine Cells
Rooney S, Alt FW, Lombard D, Whitlow S, Eckersdorff M, Fleming J, Fugmann S, Ferguson DO, Schatz DG, Sekiguchi J. Defective DNA Repair and Increased Genomic Instability in Artemis-deficient Murine Cells. Journal Of Experimental Medicine 2003, 197: 553-565. PMID: 12615897, PMCID: PMC2193825, DOI: 10.1084/jem.20021891.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsBleomycinCell LineChromosome AberrationsDNADNA DamageDNA RepairDNA-Binding ProteinsEmbryo, MammalianEndonucleasesGene TargetingGenomeHomeodomain ProteinsHumansIn Situ Hybridization, FluorescenceMiceMutationNuclear ProteinsRadiation, IonizingRecombination, GeneticSequence Analysis, DNASevere Combined ImmunodeficiencyStem CellsTelomere
2002
Evidence of a critical architectural function for the RAG proteins in end processing, protection, and joining in V(D)J recombination
Tsai CL, Drejer AH, Schatz DG. Evidence of a critical architectural function for the RAG proteins in end processing, protection, and joining in V(D)J recombination. Genes & Development 2002, 16: 1934-1949. PMID: 12154124, PMCID: PMC186421, DOI: 10.1101/gad.984502.Peer-Reviewed Original ResearchAlanineAmino Acid SubstitutionAnimalsCell LineCysteineDNADNA NucleotidyltransferasesDNA-Binding ProteinsGene Rearrangement, B-LymphocyteGenes, RAG-1Glutamic AcidHomeodomain ProteinsHumansMacromolecular SubstancesMiceMutagenesis, Site-DirectedNuclear ProteinsNucleic Acid ConformationPhenotypeProtein Interaction MappingRecombinant Fusion ProteinsRecombination, GeneticRegulatory Sequences, Nucleic AcidSerineSubstrate SpecificityVDJ Recombinases
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
1999
A dimer of the lymphoid protein RAG1 recognizes the recombination signal sequence and the complex stably incorporates the high mobility group protein HMG2
Rodgers K, Villey I, Ptaszek L, Corbett E, Schatz D, Coleman J. A dimer of the lymphoid protein RAG1 recognizes the recombination signal sequence and the complex stably incorporates the high mobility group protein HMG2. Nucleic Acids Research 1999, 27: 2938-2946. PMID: 10390537, PMCID: PMC148510, DOI: 10.1093/nar/27.14.2938.Peer-Reviewed Original ResearchConceptsRecombination signal sequencesSignal sequenceCore RAG1RAG1/RAG2 complexAbsence of RAG2Lymphoid-specific proteinsElectrophoretic mobility shift assaysSingle recombination signal sequencesMobility shift assaysRAG1 proteinProteins RAG1DNA sequencesMinimal speciesShift assaysOligomeric complexesHeptamer sequenceCompetition assaysRAG1Escherichia coliOligomeric formsRAG2Cleavage activityHMG2ProteinJ region