DNA REPAIR AND SOMATIC MUTATION IN ANTIBODY VARIABLE GENES

可变（V）基因的体细胞超突变， 编码免疫球蛋白分子的一部分，发生在 频率是其他突变的一百万倍。 基因.引入这些突变的分子机制是 未知该项目有两个主要目标。第一个目标是 研究DNA修复酶缺陷小鼠的超突变， 看看突变的频率和模式是否与 野生型小鼠小鼠V基因突变频率 核苷酸切除修复蛋白XPA缺陷，和 错配修复蛋白PMS2、MSH2和MLH1与 野生型小鼠，表明这些修复都没有 途径产生超突变。然而， 在错配修复缺陷小鼠中， 与野生型小鼠相比。结果提示 超突变途径经常引入串联突变 然后通过PMS 2相关修复过程来校正，以及 经常突变G C碱基对，然后通过 MSH2依赖性通路。第二个目标是分析 老年人和年轻人的V基因超突变，以确定 基因突变的频率或模式是否会随年龄而改变。的 两组的突变频率相同，表明 老年人有高度变异的抗体， 抗原老年人的突变谱不同于 这表明错配修复减少， 随年龄

Somatic hypermutation of variable (V) genes, which encode a portion of immunoglobulin molecules, occurs at a frequency that is a million times greater than mutation in other genes. The molecular mechanism that introduces these mutations is unknown. The project had two major aims. The first goal was to study hypermutation in mice deficient for DNA repair enzymes to see if the frequency and pattern of mutation was different from wildtype mice. The frequency of mutation in V genes from mice deficient for the nucleotide excision repair protein, XPA, and mismatch repair proteins, PMS2, MSH2, and MLH1, was similar to that of wildtype mice, indicating that neither of these repair pathways generates hypermutation. However, the pattern of mutation was altered in the mismatch repair-deficient mice compared to wildtype mice. The results suggest that the hypermutation pathway frequently introduces tandem mutations which are then corrected by a PMS2-dependent repair process, and frequently mutates G C basepairs which are then corrected by a MSH2-dependent pathway. The second goal was to analyze hypermutation in V genes from old and young humans to determine if the frequency or pattern of mutation changes with age. The frequency of mutation was identical in both groups, indicating that old humans have hypermutated antibodies with high affinity for antigens. The spectra of mutation in old humans was different than that of young humans, suggesting that mismatch repair decreases with age.