AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification.
After gene rearrangement, immunoglobulin variable genes are diversified by somatic hypermutation or gene conversion, whereas the constant region is altered by class-switch recombination. All three processes depend on activation-induced cytidine deaminase (AID), a B-cell-specific protein that has been proposed (because of sequence homology) to function by RNA editing. But indications that the three gene diversification processes might be initiated by a common type of DNA lesion, together with the proposal that there is a first phase of hypermutation that targets dC/dG, suggested to us that AID may function directly at dC/dG pairs. Here we show that expression of AID in Escherichia coli gives a mutator phenotype that yields nucleotide transitions at dC/dG in a context-dependent manner. Mutation triggered by AID is enhanced by a deficiency of uracil-DNA glycosylase, which indicates that AID functions by deaminating dC residues in DNA. We propose that diversification of functional immunoglobulin genes is triggered by AID-mediated deamination of dC residues in the immunoglobulin locus with the outcome--that is, hypermutation phases 1 and 2, gene conversion or switch recombination--dependent on the way in which the initiating dU/dG lesion is resolved.
Petersen-Mahrt
Svend K
SK
Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
Harris
Reuben S
RS
Neuberger
Michael S
MS
D000586:Amination; D000595:Amino Acid Sequence; D001483:Base Sequence; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D045647:DNA Glycosylases; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000235:genetics; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics*; D005785:Gene Conversion / Q000235:genetics; D005787:Gene Frequency; D005798:Genes, Bacterial / Q000235:genetics; D005803:Genes, Immunoglobulin / Q000235:genetics; D006801:Humans; D007134:Immunoglobulin Switch Region / Q000235:genetics; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000235:genetics*; D009699:N-Glycosyl Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D017422:Sequence Analysis, DNA; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*; D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D004269:DNA, Bacterial; D004247:DNA; D012321:DNA-Directed RNA Polymerases; C105078:RNA polymerase beta subunit; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase