Featured Publications
Structural basis for the activation and suppression of transposition during evolution of the RAG recombinase
Zhang Y, Corbett E, Wu S, Schatz DG. Structural basis for the activation and suppression of transposition during evolution of the RAG recombinase. The EMBO Journal 2020, 39: embj2020105857. PMID: 32945578, PMCID: PMC7604617, DOI: 10.15252/embj.2020105857.Peer-Reviewed Original ResearchConceptsTarget site DNASite DNARAG1/RAG2 recombinaseSuppression of transpositionCryo-electron microscopyStrand transfer complexAntigen receptor genesDomesticated transposaseTarget DNARAG recombinaseEvolutionary adaptationPaste transpositionStructural basisTransposition activityMechanistic principlesFunctional assaysTransposon endDNAReceptor geneBase unstackingDomesticationTransposaseRecombinaseAdaptive immunityFinal stepStructural insights into the evolution of the RAG recombinase
Liu C, Zhang Y, Liu CC, Schatz DG. Structural insights into the evolution of the RAG recombinase. Nature Reviews Immunology 2021, 22: 353-370. PMID: 34675378, DOI: 10.1038/s41577-021-00628-6.Peer-Reviewed Original ResearchConceptsRAG recombinaseComparative genome analysisGenomes of eukaryotesProtein-DNA complexesSingle amino acid mutationAntigen receptor genesMolecular domesticationRag familyAmino acid mutationsJawed vertebratesVertebrate immunityTransposable elementsEvolutionary adaptationGenome analysisStructural biologyDNA bindingStructural insightsGene 1Acid mutationsCleavage activityRecombinaseReceptor geneStructural evidenceRecombinationAdaptive immunity
2020
Sequence-dependent dynamics of synthetic and endogenous RSSs in V(D)J recombination
Hirokawa S, Chure G, Belliveau NM, Lovely GA, Anaya M, Schatz DG, Baltimore D, Phillips R. Sequence-dependent dynamics of synthetic and endogenous RSSs in V(D)J recombination. Nucleic Acids Research 2020, 48: gkaa418-. PMID: 32449932, PMCID: PMC7337519, DOI: 10.1093/nar/gkaa418.Peer-Reviewed Original Research
2017
New insights into the evolutionary origins of the recombination‐activating gene proteins and V(D)J recombination
Carmona LM, Schatz DG. New insights into the evolutionary origins of the recombination‐activating gene proteins and V(D)J recombination. The FEBS Journal 2017, 284: 1590-1605. PMID: 27973733, PMCID: PMC5459667, DOI: 10.1111/febs.13990.Peer-Reviewed Original ResearchConceptsTransposable elementsEvolutionary originRAG proteinsAbsence of RAG2Independent evolutionary originsBasal chordate amphioxusRecombination-activating gene (RAG) proteinsFamily of transposasesAntigen receptor genesRAG transposonChordate amphioxusJawed vertebratesSequence similarityEvolutionary relativesProteins RAG1RAG genesGene proteinRAG1Gene segmentsDiverse arrayMechanistic linkProteinRAG2Adaptive immune systemDNA cleavage reaction
2016
Collaboration of RAG2 with RAG1-like proteins during the evolution of V(D)J recombination
Carmona LM, Fugmann SD, Schatz DG. Collaboration of RAG2 with RAG1-like proteins during the evolution of V(D)J recombination. Genes & Development 2016, 30: 909-917. PMID: 27056670, PMCID: PMC4840297, DOI: 10.1101/gad.278432.116.Peer-Reviewed Original ResearchConceptsRecombination-activating gene 1Transib transposaseAbsence of RAG2RAG1/RAG2Antigen receptor genesJawed vertebratesRAG2 proteinsTransposable elementsRAG1 proteinRegulatory featuresDNA substratesGene 1RAG2Receptor geneRecombination activityProteinRecombinationTransposaseAdaptive immunityVertebratesTransposonGenesEvolutionLow levelsOrigin
2015
Chromosomal Loop Domains Direct the Recombination of Antigen Receptor Genes
Hu J, Zhang Y, Zhao L, Frock RL, Du Z, Meyers RM, Meng FL, Schatz DG, Alt FW. Chromosomal Loop Domains Direct the Recombination of Antigen Receptor Genes. Cell 2015, 163: 947-959. PMID: 26593423, PMCID: PMC4660266, DOI: 10.1016/j.cell.2015.10.016.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCCCTC-Binding FactorChromosomes, MammalianDNA-Binding ProteinsGenes, mycGenomeHigh-Throughput Nucleotide SequencingHomeodomain ProteinsHumansImmunoglobulin Heavy ChainsLymphomaMiceNucleotide MotifsRegulatory Sequences, Nucleic AcidRepressor ProteinsSequence Analysis, DNATranslocation, GeneticV(D)J RecombinationConceptsRecombination signal sequencesRSS pairAntigen receptor genesSignal sequenceRAG activityDNA breaksChromosomal loopsLoop domainBiological processesConvergent CTCFChromosomal translocationsCleavage siteReceptor geneTarget activitySuch breaksMarked orientation dependenceRecombinationRAGCTCFChromatinMegabasesOff-target distributionGenesBreaksDomainChapter One Regulation and Evolution of the RAG Recombinase
Teng G, Schatz DG. Chapter One Regulation and Evolution of the RAG Recombinase. Advances In Immunology 2015, 128: 1-39. PMID: 26477364, DOI: 10.1016/bs.ai.2015.07.002.Peer-Reviewed Original ResearchConceptsRAG activityOverall genome integrityDNA breakageSpecific DNA motifsAntigen receptor lociDNA repair pathwaysChapter One RegulationAntigen receptor genesEarly lymphocyte developmentCell cycle statusGenome integrityChromatin structureRAG recombinaseRAG2 proteinsDNA motifsSpatial regulationWidespread bindingRepair pathwaysDNA cleavage activityRecombination eventsShuffling reactionEnzymatic potentialRAG endonucleaseReceptor locusLymphocyte developmentSingle-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 geneCleavageRAGAssaysRAG1/2ComplexesSpatio-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
The RAG Recombinase Dictates Functional Heterogeneity and Cellular Fitness in Natural Killer Cells
Karo JM, Schatz DG, Sun JC. The RAG Recombinase Dictates Functional Heterogeneity and Cellular Fitness in Natural Killer Cells. Cell 2014, 159: 94-107. PMID: 25259923, PMCID: PMC4371485, DOI: 10.1016/j.cell.2014.08.026.Peer-Reviewed Original ResearchConceptsRecombination-activating geneDNA damage response mediatorsInnate lymphoid cellsNatural killer cellsAntigen receptor genesCellular fitnessJawed vertebratesRAG recombinaseCellular stressInnate lymphocytesNovel functionDNA breaksKiller cellsEndonuclease activityUnexpected roleCleavage eventsAdaptive immune cellsReceptor geneReduced expressionGenesFunctional heterogeneityCellsImmune cellsResponse mediatorsFitness
2011
Recombination centres and the orchestration of V(D)J recombination
Schatz DG, Ji Y. Recombination centres and the orchestration of V(D)J recombination. Nature Reviews Immunology 2011, 11: 251-263. PMID: 21394103, DOI: 10.1038/nri2941.Peer-Reviewed Original ResearchConceptsAntigen receptor genesRecombination signal sequencesSignal sequenceHigher-order chromatin architectureHistone H3 lysine 4Receptor geneAntigen receptor gene segmentsInactive nuclear compartmentsPlant homeodomain (PHD) fingerH3 lysine 4Antigen receptor lociReceptor gene segmentsEctopic recruitmentChromatin architectureChromatin structureLysine 4Active chromatinGenome instabilityHistone modificationsRAG2 proteinsThousands of sitesNuclear compartmentRecombination eventsTranscriptional activityGenomic DNA
2010
Promoters, enhancers, and transcription target RAG1 binding during V(D)J recombination
Ji Y, Little AJ, Banerjee JK, Hao B, Oltz EM, Krangel MS, Schatz DG. Promoters, enhancers, and transcription target RAG1 binding during V(D)J recombination. Journal Of Experimental Medicine 2010, 207: 2809-2816. PMID: 21115692, PMCID: PMC3005232, DOI: 10.1084/jem.20101136.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationAnimalsBinding, CompetitiveChromatin ImmunoprecipitationDNAEnhancer Elements, GeneticFemaleGene RearrangementGenes, ImmunoglobulinGenotypeHistonesHMGB1 ProteinHomeodomain ProteinsMaleMiceMice, Inbred C57BLMice, KnockoutPromoter Regions, GeneticProtein BindingReceptors, Antigen, T-Cell, alpha-betaRecombination, GeneticTranscription, GeneticVDJ Recombinases
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
Antigen receptor genes and the evolution of a recombinase
Schatz DG. Antigen receptor genes and the evolution of a recombinase. Seminars In Immunology 2004, 16: 245-256. PMID: 15522623, DOI: 10.1016/j.smim.2004.08.004.Peer-Reviewed Original ResearchConceptsAntigen receptor genesReceptor geneDNA repair factorsSite-specific recombination reactionRAG transposonVertebrate genomesJawed vertebratesEvolutionary implicationsRAG2 proteinsTransposable elementsRepair factorsGenesAdaptive immune systemHorizontal transmissionRAG1VertebratesGenomeImmune systemTransposonGermlineRecombinaseRAG2ProteinRecombination reactionRecombination
2003
A 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 geneHeptamer
1999
Transposition mediated by RAG1 and RAG2 and the evolution of the adaptive immune system
Schatz D. Transposition mediated by RAG1 and RAG2 and the evolution of the adaptive immune system. Immunologic Research 1999, 19: 169-182. PMID: 10493171, DOI: 10.1007/bf02786485.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsTransposable elementsAncestral receptor geneAdaptive immune systemReceptor gene segmentsReceptor geneAntigen receptor genesRAG proteinsRAG2 proteinsChromosomal DNAFunctional transposaseMillion yearsGene segmentsRAG1Dramatic supportImmune systemGenesRecent findingsUnusual structureProteinVertebratesTransposaseRAG2DNAEvolutionRecombinationDevelopmental neurobiology: Alternative ends for a familiar story?
Chun J, Schatz D. Developmental neurobiology: Alternative ends for a familiar story? Current Biology 1999, 9: r251-r253. PMID: 10209111, DOI: 10.1016/s0960-9822(99)80156-0.Commentaries, Editorials and Letters
1997
A Basic Motif in the N-Terminal Region of RAG1 Enhances V(D)J Recombination Activity
McMahan C, Difilippantonio M, Rao N, Spanopoulou E, Schatz D. A Basic Motif in the N-Terminal Region of RAG1 Enhances V(D)J Recombination Activity. Molecular And Cellular Biology 1997, 17: 4544-4552. PMID: 9234712, PMCID: PMC232308, DOI: 10.1128/mcb.17.8.4544.Peer-Reviewed Original ResearchConceptsBasic amino acid motifN-terminal regionSite-specific DNA recognitionRecombination activityCell-specific componentsComponent gene segmentsExtrachromosomal recombination substratesAmino acid motifsAmino acids 216Site-specific recombination reactionAntigen receptor genesEvolutionary conservationNuclear transportRAG2 proteinsRAG1 proteinRecombination functionsRecombination substratesDeletion analysisDNA recognitionEnzymatic machineryAcid motifFurther mutagenesisSRP-1N-terminusRAG1
1996
Neoteny in Lymphocytes: Rag1 and Rag2 Expression in Germinal Center B Cells
Han S, Zheng B, Schatz D, Spanopoulou E, Kelsoe G. Neoteny in Lymphocytes: Rag1 and Rag2 Expression in Germinal Center B Cells. Science 1996, 274: 2094-2097. PMID: 8953043, DOI: 10.1126/science.274.5295.2094.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesDNA NucleotidyltransferasesDNA-Binding ProteinsFemaleGene ExpressionGene RearrangementGenes, ImmunoglobulinGenes, RAG-1Germinal CenterHomeodomain ProteinsImmunizationImmunoglobulin Class SwitchingLymphocyte ActivationMiceMice, Inbred C57BLPolymerase Chain ReactionProtein BiosynthesisProteinsVDJ RecombinasesConceptsGerminal center B cellsAntigen receptor genesT cell antigen receptor genesRAG2 proteinsB cellsRAG2 geneRAG genesRAG2 expressionFunctional immunoglobulinPeyer's patch germinal centersMessenger RNAGenesRAG1Receptor geneActivated B cellsNormal adult animalsLymphocyte populationsImmature lymphocytesGerminal centersBone marrowMurine splenicAntibody repertoireCellsAdult animalsExpressionInitiation of V(D)J recombination in vitro obeying the 12/23 rule
Eastman Q, Leu T, Schatz D. Initiation of V(D)J recombination in vitro obeying the 12/23 rule. Nature 1996, 380: 85-88. PMID: 8598914, DOI: 10.1038/380085a0.Peer-Reviewed Original Research