Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice
Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice
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DOI：
10.1016/s0960-9822(02)01215-0
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发表时间：
2002-10-15
期刊：
影响因子：
9.2
通讯作者：
Neuberger, MS
中科院分区：
文献类型：
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作者：
Rada, C;Williams, GT;Neuberger, MS
背景：我们先前曾提出，激活诱导的胞苷脱氨酶（AID）使免疫球蛋白基因座内的胞嘧啶脱氨转变为尿嘧啶，从而触发抗体多样化。多样化的模式（第1阶段或第2阶段的超突变、基因转换或类别转换重组）被视为取决于dU/dG损伤的解决方式。一种主要的解决方式涉及切除尿嘧啶，在小鼠中至少有四种不同的酶可以完成这一活动。
结果：仅LING尿嘧啶 - DNA糖基化酶缺乏就足以使小鼠的超突变途径发生扭曲。在ung（-/-）动物中，dC/dG碱基对处的突变显著偏向转换（95%），这表明无碱基位点（可诱导颠换）的产生受到了抑制。dA/dT碱基对处的替换模式未受影响。类别转换重组被大幅抑制，但并非完全被抑制。
结论：这些结果为抗体多样化的DNA脱氨模型在类别转换以及超突变方面提供了有力支持，并且在该模型的背景下表明：（i）UNG是负责处理免疫球蛋白基因座内程序性dU/dG损伤的主要小鼠DNA糖基化酶；（ii）突变的第二阶段（偏向dAMT）可能是由对起始dU/dG损伤的识别所触发；（iii）类别转换重组主要通过无碱基位点的形成来进行，尽管（iv）存在一种不依赖UNG的类别转换重组途径，这可能反映了另一种尿嘧啶 - DNA糖基化酶的作用，但也可能由一种不同的解决途径来解释，例如一种涉及MSH2/MSH6对dU/dG损伤识别的途径。
Background: We have previously proposed that deamination of cytosine to uracil at sites within the immunoglobulin loci by activation-induced deaminase (AID) triggers antibody diversification. The pattern of diversification (phase 1 or 2 hypermutation, gene conversion, or switch recombination) is viewed as depending on the mode of resolution of the dU/dG lesion. A major resolution mode involves excising the uracil, an activity that at least four different enzymes can accomplish in the mouse.Results: Deficiency in LING uracil-DNA glycosylase alone is sufficient to distort the pathway of hypermutation in mice. In ung(-/-) animals, mutations at dC/dG pairs are dramatically shifted toward transitions (95%), indicating that the generation of abasic sites (which can induce transversions) has been inhibited. The pattern of substitutions at dA/dT pairs is unaffected. Class-switch recombination is substantially, but not totally, inhibited.Conclusions: The results provide strong support for the DNA deamination model for antibody diversification with respect to class-switching as well as hypermutation and, in the context of this model, suggest that (i) UNG is the major mouse DNA glycosylase responsible for processing the programmed dU/dG lesions within the immunoglobulin locus; (ii) the second (dAMT-biased) phase of mutation is probably triggered by recognition of the initiating dU/dG lesion; and (iii) switch recombination largely proceeds via formation of an abasic site, although (iv) an UNG-independent pathway of switch recombination exists, which could reflect action by another uracil-DNA glycosylase but might alternatively be explained by a distinct pathway of resolution, for example, one involving MSH2/MSH6 recognition of the dU/dG lesion.