Petersen-Mahrt Svend K, Harris Reuben S, Neuberger Michael S
Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
Nature. 2002 Jul 4;418(6893):99-103. doi: 10.1038/nature00862.
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.
基因重排后，免疫球蛋白可变基因通过体细胞高频突变或基因转换实现多样化，而恒定区则通过类别转换重组发生改变。所有这三个过程都依赖于激活诱导的胞嘧啶脱氨酶（AID），这是一种B细胞特异性蛋白，因其序列同源性而被认为通过RNA编辑发挥作用。但是，有迹象表明这三个基因多样化过程可能由一种常见类型的DNA损伤引发，同时有人提出存在一个靶向dC/dG的高频突变第一阶段，这使我们认为AID可能直接作用于dC/dG碱基对。我们在此表明，AID在大肠杆菌中的表达产生了一种突变表型，该表型以依赖上下文的方式在dC/dG处产生核苷酸转换。尿嘧啶-DNA糖基化酶的缺陷增强了由AID触发的突变，这表明AID通过使DNA中的dC残基脱氨发挥作用。我们提出功能性免疫球蛋白基因的多样化是由AID介导的免疫球蛋白基因座中dC残基的脱氨引发的，其结果——即高频突变的第1和第2阶段、基因转换或类别转换重组——取决于起始dU/dG损伤的修复方式。
