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, 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 types
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
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
2019
Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting
Dinesh RK, Barnhill B, Ilanges A, Wu L, Michelson DA, Senigl F, Alinikula J, Shabanowitz J, Hunt DF, Schatz DG. Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting. European Journal Of Immunology 2019, 50: 380-395. PMID: 31821534, PMCID: PMC7202714, DOI: 10.1002/eji.201948357.Peer-Reviewed Original ResearchConceptsActivation-induced cytidine deaminaseGene conversionSomatic hypermutationIg genesTranscription factor family membersTrans-acting factorsFactor family membersClass switch recombinationEnhancer-like sequenceRamos B cell lineIgH intronic enhancerSecondary diversificationTranscription factorsE-boxFactor bindingChIP assaysIntronic enhancerReporter assaysB cell linesSpecific DNASwitch recombinationSHM targetingIg enhancersCytidine deaminaseNovel insights
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
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 KeywordsAnimalsB-LymphocytesBase SequenceCell 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
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 KeywordsAnimalsB-LymphocytesBinding SitesCells, 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 locusLociAID-Targeting and Hypermutation of Non-Immunoglobulin Genes Does Not Correlate with Proximity to Immunoglobulin Genes in Germinal Center B Cells
Gramlich HS, Reisbig T, Schatz DG. AID-Targeting and Hypermutation of Non-Immunoglobulin Genes Does Not Correlate with Proximity to Immunoglobulin Genes in Germinal Center B Cells. PLOS ONE 2012, 7: e39601. PMID: 22768095, PMCID: PMC3387148, DOI: 10.1371/journal.pone.0039601.Peer-Reviewed Original ResearchConceptsNon-Ig genesC-MycIg genesAID targetingGerminal center B cellsDouble-strand break endsImportant regulatory elementsNon-immunoglobulin genesMYC transgeneHeavy chain geneRegulatory elementsBreak endsIg heavy chain genesIg lociHuman MYCGenesB cellsSuch translocationsImmunoglobulin lociImmunoglobulin genesTranslocation partnersChain geneHuman Burkitt lymphomaSomatic hypermutationNuclear position
2008
Two levels of protection for the B cell genome during somatic hypermutation
Liu M, Duke JL, Richter DJ, Vinuesa CG, Goodnow CC, Kleinstein SH, Schatz DG. Two levels of protection for the B cell genome during somatic hypermutation. Nature 2008, 451: 841-845. PMID: 18273020, DOI: 10.1038/nature06547.Peer-Reviewed Original ResearchConceptsError-free DNA repairB cell genomeGenomic stabilityNumerous oncogenesDNA repairCell genomeBase excisionGenomeMismatch repairImmunoglobulin genesSomatic hypermutationWidespread mutationsHypermutationB-cell tumorsB-cell malignanciesHigh-affinity antibodiesB cellsGenesOncogeneLarge fractionDiversityVital roleMutationsEnzymeRepair
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 AS38Strand-Biased Spreading of Mutations During Somatic Hypermutation
Unniraman S, Schatz DG. Strand-Biased Spreading of Mutations During Somatic Hypermutation. Science 2007, 317: 1227-1230. PMID: 17761884, DOI: 10.1126/science.1145065.Peer-Reviewed Original ResearchTargeting of AID‐Mediated Sequence Diversification by cis‐Acting Determinants
Yang SY, Schatz DG. Targeting of AID‐Mediated Sequence Diversification by cis‐Acting Determinants. Advances In Immunology 2007, 94: 109-125. PMID: 17560273, DOI: 10.1016/s0065-2776(06)94004-8.Peer-Reviewed Original ResearchConceptsActivation-induced cytidine deaminaseSequence diversificationFeatures of chromatinTranscriptional control elementsCis-acting determinantsClass switch recombinationGene conversionDiversification processMolecular mechanismsIg lociSwitch recombinationIg genesAntibody diversityImmunoglobulin genesCytidine deaminaseSomatic hypermutationControl elementsTranscriptionGenesDiversificationRecombinationChromatinLociDiversityPermissive
2006
Roles of the Ig κ Light Chain Intronic and 3′ Enhancers in Igk Somatic Hypermutation
Inlay MA, Gao HH, Odegard VH, Lin T, Schatz DG, Xu Y. Roles of the Ig κ Light Chain Intronic and 3′ Enhancers in Igk Somatic Hypermutation. The Journal Of Immunology 2006, 177: 1146-1151. PMID: 16818772, DOI: 10.4049/jimmunol.177.2.1146.Peer-Reviewed Original ResearchMeSH Keywords3' Untranslated RegionsAnimalsB-LymphocytesCells, CulturedDown-RegulationEnhancer Elements, GeneticGene DeletionGene Expression RegulationGerminal CenterImmunoglobulin kappa-ChainsIntronsLymphocyte ActivationMiceMice, KnockoutMice, TransgenicRNA, MessengerSomatic Hypermutation, ImmunoglobulinSpleen
2005
Histone Modifications Associated with Somatic Hypermutation
Odegard VH, Kim ST, Anderson SM, Shlomchik MJ, Schatz DG. Histone Modifications Associated with Somatic Hypermutation. Immunity 2005, 23: 101-110. PMID: 16039583, DOI: 10.1016/j.immuni.2005.05.007.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationAnimalsB-LymphocytesChromatinChromatin ImmunoprecipitationCpG IslandsDNA DamageDNA MethylationHistonesImmunoglobulin Class SwitchingImmunoglobulin lambda-ChainsImmunoglobulin Light ChainsMethylationMiceMice, TransgenicPhosphorylationProtein Serine-Threonine KinasesSomatic Hypermutation, ImmunoglobulinConceptsClass switch recombinationSomatic hypermutationDistinct DNA damage responsesPhosphorylation of H2BHistone modification patternsDNA damage responseChromatin modificationsHistone modificationsKinase Mst1Histone H2BDamage responseHistone acetylationAcetylated H3Modification patternsPhosphorylated formIg lociSwitch recombinationImmunoglobulin lociH2BGammaH2AXLociHypermutationRecombinationHistonesH2AX
2004
Non‐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
2002
The Activation-induced Deaminase Functions in a Postcleavage Step of the Somatic Hypermutation Process
Papavasiliou FN, Schatz DG. The Activation-induced Deaminase Functions in a Postcleavage Step of the Somatic Hypermutation Process. Journal Of Experimental Medicine 2002, 195: 1193-1198. PMID: 11994424, PMCID: PMC2193708, DOI: 10.1084/jem.20011858.Peer-Reviewed Original ResearchConceptsActivation-induced cytidine deaminaseClass switch recombinationSomatic hypermutationDNA lesionsDownstream constant region genesCytidine deaminase motifDominant-negative formConstant region genesInitial DNA lesionsSomatic hypermutation processHeavy chain constant regionIg genesNegative formImmunoglobulin genesChain constant regionTarget sequencePoint mutationsCytidine deaminaseHypermutation processGenesAID functionRegion genesMechanistic overlapVariable regionsConstant regionSomatic Hypermutation of Immunoglobulin Genes Merging Mechanisms for Genetic Diversity
Papavasiliou FN, Schatz DG. Somatic Hypermutation of Immunoglobulin Genes Merging Mechanisms for Genetic Diversity. Cell 2002, 109: s35-s44. PMID: 11983151, DOI: 10.1016/s0092-8674(02)00706-7.Peer-Reviewed Original ResearchConceptsActivation-induced cytidine deaminaseSomatic hypermutationRNA editing enzymeDNA strand lesionsGenetic diversityEditing enzymeMolecular mechanismsRepair moleculesStrand lesionsCytidine deaminaseHypermutation processHypermutationRecent studiesModification reactionsEffective immune responseRecent advancesHigh-affinity antibodiesImmune responseDiversityEnzymePathwayMechanismDeaminaseDiscovery
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