Mismatch repair in V region mutation and isotype switching

描述(由申请人提供)：生发中心B细胞经历了高比率的体细胞突变和免疫球蛋白基因的重组，这是亲和力成熟和同型转换产生保护性抗体的原因。这些过程是由激活诱导的胞苷脱氨酶启动的，它产生G：U错配，通过复制、碱基切除修复和错配修复来产生抗体可变区和开关区的体细胞超突变所需的突变。错配修复是导致产生更有效抗体的A：T碱基突变总数的60%和大部分突变的原因。虽然错配修复通常维持基因组的完整性和稳定性，但在Ig基因，它介导了广泛的突变和重组。在这里，我们建议研究生发中心B细胞如何利用错配修复来招募容易出错的修复到免疫球蛋白基因的特定区域，同时继续维持基因组其余部分的基因组稳定性，并研究错配修复在B细胞淋巴瘤发生中的作用。我们将通过：1)确定MSH6和其他错配修复蛋白如何与增殖细胞核抗原相互作用，以招募容易出错的修复到免疫球蛋白可变和切换区，但不到生发中心B细胞的其他基因；2)比较错配修复蛋白彼此之间以及在突变和切换B细胞中与其他蛋白质的相互作用；以及3)检测在MSH6缺陷和突变的小鼠中出现的淋巴瘤的特征，以了解MSH6如何保护B细胞免受淋巴生成的影响。

DESCRIPTION (provided by applicant): Germinal center B cells undergo a high rate of somatic mutation and recombination of their immunoglobulin genes that is responsible for the affinity maturation and isotype switching that generates protective antibodies. These processes are initiated by activation induced cytidine deaminase which generates G:U mismatches that are processed by replication, base excision repair and mismatch repair to produce the mutations required for somatic hypermutation of antibody variable and switch regions. Mismatch repair is responsible for ~60% of the total mutations and most of the mutations in A:T bases that lead to production of more effective antibodies. While mismatch repair normally maintains the integrity and stability of the genome, at the Ig gene it mediates extensive mutation and recombination. Here we propose to examine how germinal center B cells use mismatch repair to recruit error prone repair to specific regions of the immunoglobulin genes while continuing to maintain genomic stability in the rest of genome and to examine role of mismatch repair in the B cell lymphomagenesis. We will do this by: 1) determining how MSH6 and the other mismatch repair proteins interact with PCNA to recruit error prone repair to the immunoglobulin variable and switch regions, but not to other genes in mutating and switching germinal center B cells; 2) comparing the interactions of the mismatch repair proteins with each other and with other proteins in mutating and switching B cells and with those interactions in other types of cells; and 3) examining the characteristics of the lymphomas that arise in MSH6 deficient and mutant mice in order to understand how MSH6 protects B cells from lymphomagenesis.