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 stepInsights into RAG Evolution from the Identification of “Missing Link” Family A RAGL Transposons
Martin E, Le Targa L, Tsakou-Ngouafo L, Fan T, Lin C, Xiao J, Huang Z, Yuan S, Xu A, Su Y, Petrescu A, Pontarotti P, Schatz D. Insights into RAG Evolution from the Identification of “Missing Link” Family A RAGL Transposons. Molecular Biology And Evolution 2023, 40: msad232. PMID: 37850912, PMCID: PMC10629977, DOI: 10.1093/molbev/msad232.Peer-Reviewed Original ResearchConceptsJawed vertebratesTransposon familyRAG1-RAG2 recombinaseRecombination signal sequencesHemichordate Ptychodera flavaMolecular domesticationSignal sequenceP. flavaDNA bindingPtychodera flavaSequence featuresTransposition activityVertebratesTransposonCritical enzymeHinge regionGenomeDomesticationFlavaProteinPivotal stepAdaptive immunityCritical intermediateRAGRAGLHMCES protects immunoglobulin genes specifically from deletions during somatic hypermutation
Wu L, Shukla V, Yadavalli AD, Dinesh RK, Xu D, Rao A, Schatz DG. HMCES protects immunoglobulin genes specifically from deletions during somatic hypermutation. Genes & Development 2022, 36: 433-450. PMID: 35450882, PMCID: PMC9067407, DOI: 10.1101/gad.349438.122.Peer-Reviewed Original ResearchStructural 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 immunityThe RAG1 N-terminal region regulates the efficiency and pathways of synapsis for V(D)J recombination
Beilinson HA, Glynn RA, Yadavalli AD, Xiao J, Corbett E, Saribasak H, Arya R, Miot C, Bhattacharyya A, Jones JM, Pongubala JMR, Bassing CH, Schatz DG. The RAG1 N-terminal region regulates the efficiency and pathways of synapsis for V(D)J recombination. Journal Of Experimental Medicine 2021, 218: e20210250. PMID: 34402853, PMCID: PMC8374863, DOI: 10.1084/jem.20210250.Peer-Reviewed Original ResearchTransposon molecular domestication and the evolution of the RAG recombinase
Zhang Y, Cheng TC, Huang G, Lu Q, Surleac MD, Mandell JD, Pontarotti P, Petrescu AJ, Xu A, Xiong Y, Schatz DG. Transposon molecular domestication and the evolution of the RAG recombinase. Nature 2019, 569: 79-84. PMID: 30971819, PMCID: PMC6494689, DOI: 10.1038/s41586-019-1093-7.Peer-Reviewed Original ResearchConceptsRAG1-RAG2 recombinaseMolecular domesticationRAG recombinaseCryo-electron microscopy structureTwo-tiered mechanismAmino acid residuesJawed vertebratesMicroscopy structureEvolutionary adaptationDNA substratesTransposition activityAcid residuesDomesticationDNA cleavageAcidic regionDiverse repertoireAdaptive immune systemRecombinaseTransposonCell receptorTransposasePivotal eventRecombinationCleavageVertebratesStructures of a RAG-like transposase during cut-and-paste transposition
Liu C, Yang Y, Schatz DG. Structures of a RAG-like transposase during cut-and-paste transposition. Nature 2019, 575: 540-544. PMID: 31723264, PMCID: PMC6872938, DOI: 10.1038/s41586-019-1753-7.Peer-Reviewed Original ResearchConceptsCryo-electron microscopy structureC-terminal tailUnique structural elementsStrand transfer complexEukaryotic cutEvolutionary progenitorsMicroscopy structureRAG recombinasePaste transpositionApo enzymeSubstrate DNAHelicoverpa zeaConformational changesEarly stepsTransposaseAdaptive immune systemDNATarget siteTransposonTarget DNAPivotal roleActive siteEnzymeTransposition processEssential componentTopologically 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
2024
The SV40 virus enhancer functions as a somatic hypermutation-targeting element with potential tumorigenic activity
Šenigl F, Soikkeli A, Prost S, Schatz D, Slavková M, Hejnar J, Alinikula J. The SV40 virus enhancer functions as a somatic hypermutation-targeting element with potential tumorigenic activity. Tumour Virus Research 2024, 18: 200293. PMID: 39490533, PMCID: PMC11564006, DOI: 10.1016/j.tvr.2024.200293.Peer-Reviewed Original ResearchB cellsSV40 LTMerkel cell polyomavirusAPOBEC familySV40 enhancerCell typesAssociated with several typesAID-induced mutationsLT expressionTumorigenic potentialMalignant developmentSV40 infectionTumorigenic activityHuman cancersSomatic hypermutationAberrant expressionAntibody diversification processesSimian virusKidney cellsMonkey virusSV40Virus enhancerMutationsFrequent sourceSeveral typesRORγt up-regulates RAG gene expression in DP thymocytes to expand the Tcra repertoire
Naik A, Dauphars D, Corbett E, Simpson L, Schatz D, Krangel M. RORγt up-regulates RAG gene expression in DP thymocytes to expand the Tcra repertoire. Science Immunology 2024, 9: eadh5318. PMID: 38489350, PMCID: PMC11005092, DOI: 10.1126/sciimmunol.adh5318.Peer-Reviewed Original ResearchConceptsRecombination activating geneDP thymocytesUp-regulatedAntigen receptor lociDouble-positive (DP) stageRAG expressionTranscriptional up-regulationDouble-negative (DNRAG gene expressionActive genesTcra repertoireReceptor locusDN thymocytesGene expressionThymocyte transitionLymphocyte developmentThymocyte proliferationPhysiological importanceMultiple pathwaysRORgtThymocytesExpressionRepertoireRecombinationAntisilencingChapter 2 The Mechanism, Regulation and Evolution of V(D)J Recombination
Schatz D, Zhang Y, Xiao J, Zha S, Zhang Y, Alt F. Chapter 2 The Mechanism, Regulation and Evolution of V(D)J Recombination. 2024, 13-57. DOI: 10.1016/b978-0-323-95895-0.00004-0.Peer-Reviewed Original ResearchAntigen receptor lociNon-homologous end joiningChromatin loop extrusionRecombination-activating geneLoop extrusionV(D)J recombinationRecombination-activating gene proteinV(D)J recombination reactionReceptor locusEnd joiningDouble-strand (ds) DNA breaksLoop extrusion mechanismRegulation of recombinationRepertoire of antigen receptorsLymphocyte developmentOncogenic chromosomal translocationsVariable region gene segmentsDNA repair proteinsDNA repair pathwaysChromatin accessibilityDNA segmentsV(D)J recombinase activitySubstrate DNALoop domainV(D)J junctionsThe Role of RAG in V(D)J Recombination
Xiao J, Martin E, Wang K, Schatz D. The Role of RAG in V(D)J Recombination. 2024 DOI: 10.1016/b978-0-128-24465-4.00019-3.Peer-Reviewed Original ResearchRecombination signal sequencesRecombination activating geneV(D)J recombinationDNA cleavageConserved sequence elementsNonhomologous end-joining pathwayLymphoid-specific proteinsAntigen receptor gene segmentsEnd-joining pathwayPair of hairpinsReceptor gene segmentsTransposable elementsDomain architectureSequence elementsLocus structureSignal sequenceTransposition mechanismTranscriptional regulationJawed vertebratesTransposase activityActive genesPosttranslational modificationsEnhancer elementsProtein structureCell cycle
2023
Dancing with DNA: AID embraces flexible partners
Wang J, Schatz D. Dancing with DNA: AID embraces flexible partners. Cell Research 2023, 33: 743-744. PMID: 37173514, PMCID: PMC10542796, DOI: 10.1038/s41422-023-00823-1.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
2021
RAG2 abolishes RAG1 aggregation to facilitate V(D)J recombination
Gan T, Wang Y, Liu Y, Schatz DG, Hu J. RAG2 abolishes RAG1 aggregation to facilitate V(D)J recombination. Cell Reports 2021, 37: 109824. PMID: 34644584, PMCID: PMC8783374, DOI: 10.1016/j.celrep.2021.109824.Peer-Reviewed Original ResearchStructural basis of mismatch recognition by a SARS-CoV-2 proofreading enzyme
Liu C, Shi W, Becker ST, Schatz DG, Liu B, Yang Y. Structural basis of mismatch recognition by a SARS-CoV-2 proofreading enzyme. Science 2021, 373: 1142-1146. PMID: 34315827, PMCID: PMC9836006, DOI: 10.1126/science.abi9310.Peer-Reviewed Original ResearchConceptsCryo-electron microscopy structureRNA synthesisCoronavirus RNA synthesisNascent RNAMicroscopy structureVirus life cycleMismatch recognitionRNA substratesSubstrate specificityStructural basisMolecular mechanismsNonstructural proteinsMolecular determinantsProofreading enzymeReplication fidelityMismatch correctionAnalogue inhibitorsLife cycleExoribonucleaseExonsComplexesRNARational designProteinEnzymeSarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity is required for V(D)J recombination
Chen CC, Chen BR, Wang Y, Curman P, Beilinson HA, Brecht RM, Liu CC, Farrell RJ, de Juan-Sanz J, Charbonnier LM, Kajimura S, Ryan TA, Schatz DG, Chatila TA, Wikstrom JD, Tyler JK, Sleckman BP. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity is required for V(D)J recombination. Journal Of Experimental Medicine 2021, 218: e20201708. PMID: 34033676, PMCID: PMC8155808, DOI: 10.1084/jem.20201708.Peer-Reviewed Original ResearchConceptsRAG2 gene expressionSarco/endoplasmic reticulum Ca2Gene expressionEndoplasmic reticulum Ca2ER Ca2ER transmembrane proteinExpression of SERCA3Mature B cellsER lumenCytosolic Ca2Transmembrane proteinCRISPR/PreB cellsDNA cleavageB cellsReticulum Ca2SERCA proteinATPase activityProteinProfound blockATP2A2 mutationsRAG1RecombinationStructural visualization of transcription activated by a multidrug-sensing MerR family regulator
Yang Y, Liu C, Zhou W, Shi W, Chen M, Zhang B, Schatz DG, Hu Y, Liu B. Structural visualization of transcription activated by a multidrug-sensing MerR family regulator. Nature Communications 2021, 12: 2702. PMID: 33976201, PMCID: PMC8113463, DOI: 10.1038/s41467-021-22990-8.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsBacterial ProteinsBase SequenceBinding SitesCloning, MolecularCryoelectron MicroscopyCrystallography, X-RayDNA, BacterialDNA-Binding ProteinsDNA-Directed RNA PolymerasesEscherichia coliGene ExpressionGene Expression Regulation, BacterialGenetic VectorsModels, MolecularNucleic Acid ConformationPromoter Regions, GeneticProtein BindingProtein Conformation, alpha-HelicalProtein Conformation, beta-StrandProtein Interaction Domains and MotifsRecombinant ProteinsTranscription Elongation, GeneticTranscription Initiation, GeneticConceptsMerR family regulatorsFamily regulatorCryo-electron microscopy structureBacterial RNA polymerase holoenzymeRegulation of transcriptionRNA polymerase holoenzymePromoter openingTranscription regulationMicroscopy structureTranscription initiationPolymerase holoenzymeRNA elongationTranscriptional regulatorsMerR familyDNA remodelingSpacer DNAPromoter recognitionPromoter elementsCellular signalsSpacer promoterInitial transcriptionTranscription processTranscriptionPromoterRegulator
2020
A Future Outlook on Molecular Mechanisms of Immunity
Weinmann AS, Youngblood BA, Smale ST, Brink R, Schatz DG, McHeyzer-Williams M. A Future Outlook on Molecular Mechanisms of Immunity. Trends In Immunology 2020, 41: 549-555. PMID: 32507312, DOI: 10.1016/j.it.2020.05.005.Peer-Reviewed Original ResearchDisease-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