Storb U, Peters A, Klotz E, Kim N, Shen H M, Hackett J, Rogerson B, Martin T E
Department of Molecular Genetics and Cell Biology, University of Chicago 60637, Illinois, USA.
Immunol Rev. 1998 Apr;162:153-60. doi: 10.1111/j.1600-065x.1998.tb01438.x.
We review our studies on the mechanism of somatic hypermutation of immunoglobulin genes. Most experiments were carried out using Ig transgenes. We showed in these experiments that all required cis-acting elements are present within the 10-16 kb of a transgene. Only the Ig variable region and its proximate flanks are mutated, not the constant region. Several Ig gene enhancers are permissive for somatic mutation. Association of the enhancer with its natural Ig promoter is not necessary. However, the mutation process seems specific for Ig genes. No mutations were found in housekeeping genes from cells with high levels of somatic hypermutation of their Ig genes. The Ig enhancers may provide the Ig gene specificity. An exception may be the BCL6 gene, which was mutated in human but not in mouse B cells. Transcription of a region is required for its mutability. When the transcriptional promoter located upstream of the variable region is duplicated upstream of the constant region, this region also becomes mutable. This suggests a model in which a mutator factor associates with the RNA polymerase at the promoter, travels with the polymerase during elongation, and causes mutations during polymerase pausing. The DNA repair systems, nucleotide excision repair and DNA mismatch repair, are not required. Our recent data with an artificial substrate of somatic mutation suggest that pausing may be due to secondary structure of the DNA or nascent RNA, and the specific mutations to preferences of the mutator factor.
我们回顾了关于免疫球蛋白基因体细胞超突变机制的研究。大多数实验是使用免疫球蛋白转基因进行的。我们在这些实验中表明，所有必需的顺式作用元件都存在于转基因的10 - 16 kb范围内。只有免疫球蛋白可变区及其紧邻侧翼发生突变，恒定区不发生突变。几种免疫球蛋白基因增强子允许体细胞突变。增强子与其天然免疫球蛋白启动子的结合并非必要。然而，突变过程似乎对免疫球蛋白基因具有特异性。在免疫球蛋白基因发生高水平体细胞超突变的细胞中，看家基因未发现突变。免疫球蛋白增强子可能提供了免疫球蛋白基因的特异性。一个例外可能是BCL6基因，它在人类B细胞中发生突变，但在小鼠B细胞中未发生突变。一个区域的转录是其可突变性所必需的。当位于可变区上游的转录启动子在恒定区上游重复时，该区域也变得可突变。这提示了一个模型，即一个诱变因子在启动子处与RNA聚合酶结合，在延伸过程中与聚合酶一起移动，并在聚合酶暂停时引起突变。DNA修复系统，即核苷酸切除修复和DNA错配修复，并非必需。我们最近关于体细胞突变人工底物的数据表明，暂停可能是由于DNA或新生RNA的二级结构，以及诱变因子的特异性突变偏好所致。
