Recombinogenic phenotype of human activation-induced cytosine deaminase.
Class switch recombination, gene conversion, and somatic hypermutation that diversify rearranged Ig genes to produce various classes of high affinity Abs are dependent on the enzyme activation-induced cytosine deaminase (AID). Evidence suggests that somatic hypermutation is due to error-prone DNA repair that is initiated by AID-mediated deamination of cytosine in DNA, whereas the mechanism by which AID controls recombination remains to be elucidated. In this study, using a yeast model system, we have observed AID-dependent recombination. Expression of human AID in wild-type yeast is mutagenic for G-C to A-T transitions, and as expected, this mutagenesis is increased upon inactivation of uracil-DNA glycosylase. AID expression also strongly induces intragenic mitotic recombination, but only in a strain possessing uracil-DNA glycosylase. Thus, the initial step of base excision repair is required for AID-dependent recombination and is a branch point for either hypermutagenesis or recombination.
Poltoratsky
Vladimir P
VP
Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Wilson
Samuel H
SH
Kunkel
Thomas A
TA
Pavlov
Youri I
YI
D020137:Base Pair Mismatch; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000235:genetics*; D003596:Cytosine / Q000378:metabolism; D004260:DNA Repair; D004790:Enzyme Induction / Q000276:immunology; D006801:Humans; D017578:Immunoglobulin Class Switching; D008213:Lymphocyte Activation / Q000235:genetics; D016296:Mutagenesis; D010641:Phenotype; D017393:RNA Editing; D011995:Recombination, Genetic / Q000276:immunology; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin; D020798:Two-Hybrid System Techniques; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D003596:Cytosine; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase