Featured Publications
Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation
Senigl F, Maman Y, Dinesh RK, Alinikula J, Seth RB, Pecnova L, Omer AD, Rao SSP, Weisz D, Buerstedde JM, Aiden EL, Casellas R, Hejnar J, Schatz DG. Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation. Cell Reports 2019, 29: 3902-3915.e8. PMID: 31851922, PMCID: PMC6980758, DOI: 10.1016/j.celrep.2019.11.039.Peer-Reviewed Original Research
2022
Ig Enhancers Increase RNA Polymerase II Stalling at Somatic Hypermutation Target Sequences.
Tarsalainen A, Maman Y, Meng FL, Kyläniemi MK, Soikkeli A, Budzyńska P, McDonald JJ, Šenigl F, Alt FW, Schatz DG, Alinikula J. Ig Enhancers Increase RNA Polymerase II Stalling at Somatic Hypermutation Target Sequences. The Journal Of Immunology 2022, 208: 143-154. PMID: 34862258, PMCID: PMC8702490, DOI: 10.4049/jimmunol.2100923.Peer-Reviewed Original ResearchConceptsPol IIMutating geneSomatic hypermutationTarget genesChicken DT40 B cellsRNA polymerase II stallingIg genesHistone variant H3.3Locus-specific targetingPol II occupancyAID-mediated mutationsDT40 B cellsRNA polymerase IILevels of H3K27acFull-length transcriptsVariant H3.3Antisense transcriptionTranscriptional outputPolymerase IIGenetic diversityMechanistic basisBurkitt's lymphoma cellsGeneration of AbsGenesDIVAC
2016
Modeling altered T-cell development with induced pluripotent stem cells from patients with RAG1-dependent immune deficiencies
Brauer PM, Pessach IM, Clarke E, Rowe JH, Ott de Bruin L, Lee YN, Dominguez-Brauer C, Comeau AM, Awong G, Felgentreff K, Zhang YH, Bredemeyer A, Al-Herz W, Du L, Ververs F, Kennedy M, Giliani S, Keller G, Sleckman BP, Schatz DG, Bushman FD, Notarangelo LD, Zúñiga-Pflücker JC. Modeling altered T-cell development with induced pluripotent stem cells from patients with RAG1-dependent immune deficiencies. Blood 2016, 128: 783-793. PMID: 27301863, PMCID: PMC4982452, DOI: 10.1182/blood-2015-10-676304.Peer-Reviewed Original ResearchConceptsInduced pluripotent stem cellsT cell developmentPluripotent stem cellsT cell receptorStem cellsOmenn syndrome patientsSingle-strand DNA breaksHuman induced pluripotent stem cellsControl iPSCsDeep-sequencing analysisT lineage cellsHuman T-cell developmentT cell progenitorsIPSC-derived cellsJoining genesImpaired T-cell differentiationDNA breaksSame geneN-terminalImmune system developmentLocus rearrangementT cell differentiationPatient cellsRecombination activityGenetic defects
2015
Single-molecule analysis of RAG-mediated V(D)J DNA cleavage
Lovely GA, Brewster RC, Schatz DG, Baltimore D, Phillips R. Single-molecule analysis of RAG-mediated V(D)J DNA cleavage. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: e1715-e1723. PMID: 25831509, PMCID: PMC4394307, DOI: 10.1073/pnas.1503477112.Peer-Reviewed Original ResearchConceptsRecombination signal sequencesSingle-molecule assaysSame DNA moleculeAntigen receptor genesConsensus recombination signal sequencesSingle-molecule analysisHigh mobility group box protein 1Individual molecular eventsSignal sequenceSingle-molecule levelGene productsDNA bindingMolecular eventsLymphocyte developmentDNA moleculesDNA cleavageProtein 1Synapse formationSynaptic complexReceptor geneCleavageRAGAssaysRAG1/2ComplexesMapping and Quantitation of the Interaction between the Recombination Activating Gene Proteins RAG1 and RAG2* ♦
Zhang YH, Shetty K, Surleac MD, Petrescu AJ, Schatz DG. Mapping and Quantitation of the Interaction between the Recombination Activating Gene Proteins RAG1 and RAG2* ♦. Journal Of Biological Chemistry 2015, 290: 11802-11817. PMID: 25745109, PMCID: PMC4424321, DOI: 10.1074/jbc.m115.638627.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCatalytic DomainDNA-Binding ProteinsGene Expression RegulationGenome, HumanHEK293 CellsHomeodomain ProteinsHumansInterferometryMaleMiceMice, Inbred C57BLMolecular Sequence DataMutationNuclear ProteinsProtein BindingProtein Interaction MappingProtein Structure, SecondaryThymus GlandV(D)J RecombinationVDJ RecombinasesConceptsRegion of RAG1Α-helixZinc finger regionResidues N-terminalActive siteAcidic amino acidsPulldown assaysAccessory factorsHermes transposaseProteins RAG1Finger regionRAG activityQuantitative Western blottingC-terminusRAG endonucleaseN-terminalCatalytic functionRAG1Amino acidsDNA cleavageRAG2Nuclear concentrationRecombination activityCatalytic centerBiolayer interferometrySpatio-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
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 mutationsEnhancerTranscription
2013
A Critical Context-Dependent Role for E Boxes in the Targeting of Somatic Hypermutation
McDonald JJ, Alinikula J, Buerstedde JM, Schatz DG. A Critical Context-Dependent Role for E Boxes in the Targeting of Somatic Hypermutation. The Journal Of Immunology 2013, 191: 1556-1566. PMID: 23836058, PMCID: PMC3735716, DOI: 10.4049/jimmunol.1300969.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesB-LymphocytesCells, CulturedChickensCytidine DeaminaseDNA, RecombinantE-Box ElementsEnhancer Elements, GeneticGenes, Immunoglobulin Light ChainGenes, ReporterGreen Fluorescent ProteinsImmunoglobulin Variable RegionMutationProtein BindingSomatic Hypermutation, ImmunoglobulinTranscription Factor 3TransfectionTransgenesConceptsE-boxSomatic hypermutationChicken DT40 B cellsDT40 B cellsNon-Ig lociOff-target mutationsActivation-induced cytidine deaminaseContext-dependent roleShort DNA sequencesSequence motifsDNA sequencesTarget genesIg genesSequence contextAffinity of AbsDNA damageCytidine deaminaseRepertoire diversificationMutationsGenesMotifSequenceFunctional hierarchyHypermutationAg stimulation
2012
Identification of Core DNA Elements That Target Somatic Hypermutation
Kohler KM, McDonald JJ, Duke JL, Arakawa H, Tan S, Kleinstein SH, Buerstedde JM, Schatz DG. Identification of Core DNA Elements That Target Somatic Hypermutation. The Journal Of Immunology 2012, 189: 5314-5326. PMID: 23087403, PMCID: PMC3664039, DOI: 10.4049/jimmunol.1202082.Peer-Reviewed Original ResearchMeSH Keywords3' Flanking RegionAnimalsB-LymphocytesCells, CulturedChickensChromatin ImmunoprecipitationCytidine DeaminaseDNAEnhancer Elements, GeneticGenes, ImmunoglobulinGenetic LociImmunoassayImmunoglobulin Variable RegionMutationPhosphorylationRNA Polymerase IISerineSomatic Hypermutation, ImmunoglobulinTranscription, GeneticConceptsActivation-induced deaminaseDNA elementsSomatic hypermutationChicken DT40 B cellsIg lociChromatin immunoprecipitation experimentsDT40 B cellsRNA polymerase IISystematic deletion analysisL chain lociNon-Ig genesCore DNA elementSerine 5Epigenetic marksPolymerase IITranscriptional elongationMutational machineryDeletion analysisReporter cassetteImmunoprecipitation experimentsDeoxycytosine residuesIg genesDNA damageChain locusLoci
2009
Imatinib Resistance and Progression of CML to Blast Crisis: Somatic Hypermutation AIDing the Way
Strout MP, Schatz DG. Imatinib Resistance and Progression of CML to Blast Crisis: Somatic Hypermutation AIDing the Way. Cancer Cell 2009, 16: 174-176. PMID: 19732715, DOI: 10.1016/j.ccr.2009.08.012.Peer-Reviewed Original ResearchConceptsChronic myeloid leukemiaProgression of CMLColleagues present evidenceDisease progressionImatinib resistanceMyeloid leukemiaDrug resistanceCancer cellsOncogenic mutationsProgressionEnzyme activation-induced deaminaseGeneration of mutationsLeukemiaMutationsActivation-induced deaminasePresent evidenceBalancing AID and DNA repair during somatic hypermutation
Liu M, Schatz DG. Balancing AID and DNA repair during somatic hypermutation. Trends In Immunology 2009, 30: 173-181. PMID: 19303358, DOI: 10.1016/j.it.2009.01.007.Peer-Reviewed Original Research
2007
Activation-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
Control of gene conversion and somatic hypermutation by immunoglobulin promoter and enhancer sequences
Yang SY, Fugmann SD, Schatz DG. Control of gene conversion and somatic hypermutation by immunoglobulin promoter and enhancer sequences. Journal Of Experimental Medicine 2006, 203: 2919-2928. PMID: 17178919, PMCID: PMC2118177, DOI: 10.1084/jem.20061835.Peer-Reviewed Original ResearchActinsAnimalsBacteriophage T7B-LymphocytesCell Line, TumorCytidine DeaminaseEnhancer Elements, GeneticGene ConversionGene DeletionGene ExpressionGenes, Immunoglobulin Light ChainImmunoglobulin Heavy ChainsImmunoglobulin MMutationPeptide Elongation Factor 1Promoter Regions, GeneticReceptors, Antigen, B-CellSomatic Hypermutation, ImmunoglobulinTranscription, GeneticTransfection
2004
Identification of an AID-independent pathway for chromosomal translocations between the Igh switch region and Myc
Unniraman S, Zhou S, Schatz DG. Identification of an AID-independent pathway for chromosomal translocations between the Igh switch region and Myc. Nature Immunology 2004, 5: 1117-1123. PMID: 15489857, DOI: 10.1038/ni1127.Peer-Reviewed Original ResearchUNGstoppable Switching
Unniraman S, Fugmann SD, Schatz DG. UNGstoppable Switching. Science 2004, 305: 1113-1114. PMID: 15326342, DOI: 10.1126/science.1102692.Peer-Reviewed Original ResearchNon‐redundancy of cytidine deaminases in class switch recombination
Fugmann SD, Rush JS, Schatz DG. Non‐redundancy of cytidine deaminases in class switch recombination. European Journal Of Immunology 2004, 34: 844-849. PMID: 14991614, DOI: 10.1002/eji.200324418.Peer-Reviewed Original ResearchConceptsActivation-induced cytidine deaminaseClass switch recombinationAPOBEC-1Human activation-induced cytidine deaminaseSwitch recombinationCognate substratesCatalytic mutantGene conversionClose homologueProkaryotic cellsInactive mutantMurine B cellsDistinct mRNAsCytidine deaminase activityCytidine deaminasesImmunoglobulin genesDiversification mechanismsCytidine deaminaseSomatic hypermutationUnknown mechanismDeaminase activityMutantsPrecise roleActivated B cellsB cells
2003
Defective 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
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 regionDetection of RAG Protein-V(D)J Recombination Signal Interactions Near the Site of DNA Cleavage by UV Cross-Linking
Eastman Q, Villey I, Schatz D. Detection of RAG Protein-V(D)J Recombination Signal Interactions Near the Site of DNA Cleavage by UV Cross-Linking. Molecular And Cellular Biology 1999, 19: 3788-3797. PMID: 10207102, PMCID: PMC84213, DOI: 10.1128/mcb.19.5.3788.Peer-Reviewed Original ResearchConceptsRecombination signal sequencesRAG proteinsRAG2 proteinsDNA cleavageHeptamer elementSite of cleavageActive site organizationRAG1-RAG2RAG1 proteinSignal sequenceDouble-strand cleavageSite-specific interactionsSame nucleotideRecognition surfaceProteinRAG1UV CrossSignal interactionsSite organizationCleavageSequenceComplexesSitesClose proximityNucleotides