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
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
Dendritic cell–mediated activation-induced cytidine deaminase (AID)–dependent induction of genomic instability in human myeloma
Koduru S, Wong E, Strowig T, Sundaram R, Zhang L, Strout MP, Flavell RA, Schatz DG, Dhodapkar KM, Dhodapkar MV. Dendritic cell–mediated activation-induced cytidine deaminase (AID)–dependent induction of genomic instability in human myeloma. Blood 2012, 119: 2302-2309. PMID: 22234692, PMCID: PMC3311257, DOI: 10.1182/blood-2011-08-376236.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternCell Line, TumorCell SurvivalCells, CulturedCoculture TechniquesCytidine DeaminaseDendritic CellsDNA Breaks, Double-StrandedFemaleGene Expression Regulation, EnzymologicGene Expression Regulation, NeoplasticGenomic InstabilityHumansInterleukin Receptor Common gamma SubunitMiceMice, Inbred NODMice, KnockoutMice, SCIDMultiple MyelomaNF-kappa BRANK LigandReverse Transcriptase Polymerase Chain ReactionTransplantation, HeterologousTumor Cells, CulturedConceptsInduction of AIDMultiple myelomaTumor microenvironmentTumor cellsReceptor activatorActivation-induced cytidine deaminaseDendritic cell infiltrationCapacity of DCPrimary MM cellsNF-κB/receptor activatorGenetics of tumorsGrowth of tumorsGenomic damageMyeloma cell linesRANKL inhibitionPlasmacytoid DCsIndolent behaviorCell infiltrationMM cellsHuman myelomaCytidine deaminaseMyelomaDNA double-strand breaksGenomic instabilityCell lines
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 featuresDeaminaseDT40TranscriptionGenesLociDNADiversificationMutabilityTargetingIgTargetTargeting 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
2005
Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination
Rush JS, Liu M, Odegard VH, Unniraman S, Schatz DG. Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination. Proceedings Of The National Academy Of Sciences Of The United States Of America 2005, 102: 13242-13247. PMID: 16141332, PMCID: PMC1201576, DOI: 10.1073/pnas.0502779102.Peer-Reviewed Original ResearchConceptsClass switch recombinationCell divisionAID expressionSwitch recombinationFrequency of CSRSingle cell divisionSubsequent cell divisionSuccessive cell divisionsActivation-induced cytidine deaminaseConstitutive AID expressionIg heavy chain constant regionsEffector function propertiesHeavy chain constant regionActivation-induced cytidine deaminase mRNAMolecular explanationMechanistic basisDifferent molecular featuresSuccessive divisionsChain constant regionCytidine deaminaseB cell activationCytokine exposureExpressionConstant regionCell activation
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 ResearchConceptsActivation-induced cytidine deaminaseB-cell malignanciesTranslocation-positive cellsChromosomal translocationsIgh switch regionsStaggered AID‐dependent DNA double strand breaks are the predominant DNA lesions targeted to Sµ in Ig class switch recombination
Rush JS, Fugmann SD, Schatz DG. Staggered AID‐dependent DNA double strand breaks are the predominant DNA lesions targeted to Sµ in Ig class switch recombination. International Immunology 2004, 16: 549-557. PMID: 15039385, DOI: 10.1093/intimm/dxh057.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalBlotting, SouthernB-LymphocytesCell DivisionCytidine DeaminaseDeoxyribonucleases, Type II Site-SpecificDNADNA DamageDNA PrimersFlow CytometryGene ExpressionImmunoglobulin Class SwitchingImmunoglobulin DImmunoglobulin GImmunoglobulin Switch RegionInterleukin-4LipopolysaccharidesMiceMice, Inbred C57BLMice, KnockoutPlasmidsPolymerase Chain ReactionRecombination, GeneticConceptsClass switch recombinationDNA double-strand breaksPredominant DNA lesionsDouble-strand breaksActivation-induced cytidine deaminaseDNA lesionsSwitch recombinationAID-dependent DNA double-strand breaksStrand breaksIg class switch recombinationLigation-mediated PCRS mu regionCellular regulationKinetics of inductionMolecular detailsMurine B cellsDNA DSBsStaggered breaksCytidine deaminaseDSBsMu regionMinor speciesB cellsS muEffector propertiesNon‐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