Activation-Induced Cytidine Deaminase Initiates Immunoglobulin Gene Conversion and Hypermutation by a Common Intermediate 英文参考文献.docVIP

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Activation-Induced Cytidine Deaminase Initiates Immunoglobulin Gene Conversion and Hypermutation by a Common Intermediate 英文参考文献.doc

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Activation-Induced Cytidine Deaminase Initiates Immunoglobulin Gene Conversion and Hypermutation by a Common Intermediate 英文参考文献

o PL S BIOLOGY Activation-InducedCytidineDeaminase InitiatesImmunoglobulinGeneConversion andHypermutationbyaCommonIntermediate Hiroshi Arakawa, Huseyin Saribasak, Jean-Marie Buerstedde* GSF–NationalResearchCenterforEnvironmentandHealth,InstituteforMolecularRadiobiology,Neuherberg-Munich,Germany Dependingonthespeciesandthelymphoidorgan,activation-inducedcytidinedeaminase(AID)expressiontriggers diversification of the rearranged immunoglobulin (Ig) genes by pseudo V (wV) gene- templated gene conversion or somatic hypermutation. To investigate how AID can alternatively induce recombination or hypermutation, wV gene deletions were introduced into the rearranged light chain locus of the DT40 B-cell line. We show that the stepwise removal of the wV donors not only reduces and eventually abolishes Ig gene conversion, but also activates AID- dependent Ig hypermutation. This strongly supports a model in which AID induces a common modification in the rearranged V(D)J segment, leading to a conversion tract in the presence of nearby donor sequences and to a point mutationintheirabsence. a defect in DNA repair by homologous recombination can shiftIggeneconversiontohypermutation. Introduction Immunoglobulin (Ig) genes are further diversi?ed after V(D)Jrearrangementbygeneconversion,hypermutation,or a combination of the two. Surprisingly, even closely related species employ different strategies: mice and humans use exclusivelyhypermutation(MilsteinandRada1995),whereas rabbits, cows, and pigs use mainly gene conversion (Butler 1998).Thebalancebetweenthetwophenomenacanalsoshift during differentiation: for example, chicken B-cells ?rst develop their Ig repertoire by gene conversion in the bursa (Reynaudetal.1987;ArakawaandBuerstedde2004)andlater ?ne tune it by hypermutation in splenic germinal centers (Arakawaetal.1996). All three B-cell speci?c activities of Ig repertoire for- mation—gene conversion (Arakawa et al. 2002), hypermuta- tion, and isotype switch recombination (Muramats