AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification

Svend K. Petersen-Mahrt, Reuben S. Harris and Michael S. Neuberger ()
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Svend K. Petersen-Mahrt: Medical Research Council Laboratory of Molecular Biology
Reuben S. Harris: Medical Research Council Laboratory of Molecular Biology
Michael S. Neuberger: Medical Research Council Laboratory of Molecular Biology

Nature, 2002, vol. 418, issue 6893, 99-104

Abstract: Abstract 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)1,2,3,4,5,6,7, a B-cell-specific protein that has been proposed (because of sequence homology1) to function by RNA editing. But indications that the three gene diversification processes might be initiated by a common type of DNA lesion8,9,10,11, together with the proposal that there is a first phase of hypermutation that targets dC/dG12, 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.

Date: 2002
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DOI: 10.1038/nature00862

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