Elucidation of Immunoglobulin Class Switch Recombination

描述(申请人提供)：成熟的B淋巴细胞经历类开关重组(CSR)，一种缺失-重组反应，取代免疫球蛋白(Ig)分子的恒定区，成为一组下游恒定区基因之一。这将表达的抗体的类别从IgM改变为免疫球蛋白、免疫球蛋白E或免疫球蛋白A，每种抗体都具有不同的效应功能。CSR发生在恒定区基因之前的称为开关(S)区的大重复序列中。CSR是由激活诱导脱氨酶(AID)启动的，AID是一种单链脱氨酶，在转录的S区域引入U：G错配。碱基切除修复和错配修复途径的后续处理在S地区引入了DNA双链断裂(DSB)。两个不同的S区域之间的DSB被突触，然后通过末端连接的方式连接起来。双链断裂是CSR的必经中间体；然而，双链断裂也构成了细胞中可能发生的最具毒性的损伤之一。单个未修复的DSB可能导致细胞死亡或参与染色体易位，这是包括淋巴瘤在内的许多类型癌症的特征。因此，CSR不仅需要DSB的产生，而且需要有效的修复。在这个建议中，我们检验了AID的磷酸化在DSB的产生中起重要作用的假设。我们还探讨了DNA损伤传感器ATM在此过程中参与诱导AID磷酸化和DSB修复的假设。CSR受损导致对病原体的反应能力受损，而CSR异常是B细胞淋巴瘤个体发生的主要潜在因素之一。因此，我们的研究将对免疫缺陷综合征和B细胞淋巴肿大产生重大影响。

DESCRIPTION (provided by applicant): Mature B-lymphocytes undergo class switch recombination (CSR), a deletional-recombination reaction that replaces the constant region of the immunoglobulin (Ig) molecule for one of a set of downstream constant region genes. This changes the class of the expressed antibody from IgM to IgG, IgE or IgA, each of which has distinct effector functions. CSR occurs within and requires large repetitive sequences termed switch (S) regions that precede the constant region genes. CSR is initiated by AID (activation induced deaminase), a single-strand DNA-specific deaminase, that introduces U:G mismatches in transcribed S regions. Subsequent processing by components of base excision repair and mismatch repair pathways introduces DNA double- stranded breaks (DSBs) in S regions. DSBs between two distinct S regions are synapsed and then ligated by end-joining. DSBs serve as obligatory intermediates of CSR; however, DSBs also constitute one of the most toxic lesions that can occur in a cell. A single unrepaired DSB can lead to cell death or can participate in chromosomal translocations, the hallmarks of many types of cancer, including lymphomas. Thus, CSR requires not only the generation but also efficient repair of DSBs. In this proposal we test the hypothesis that phosphorylation of AID plays an essential role in the generation of DSBs. We also explore the hypothesis that the DNA damage sensor ATM participates in inducing AID phosphorylation and repair of DSBs during the process. Impaired CSR leads to impaired ability to respond to pathogens while aberrant CSR is one of the major underlying factors in the ontogeny of B cell lymphomas. Our studies will thus have major impact on both immunodeficiency syndromes and B cell lymphomagenesis.