Elucidation of Immunoglobulin Class Switch Recombination

描述（由申请人提供）：成熟B淋巴细胞经历类别转换重组（CSR），这是一种缺失重组反应，将免疫球蛋白（IG）分子的恒定区替换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IgG、IgE或伊加，其中每一种具有不同的效应子功能。CSR发生在恒定区基因之前的称为开关（S）区的大的重复序列内并且需要所述大的重复序列。CSR是由AID（激活诱导脱氨酶）启动的，AID是一种单链DNA特异性脱氨酶，在转录的S区引入U：G错配。碱基切除修复和错配修复途径的组分的后续加工在S区中引入DNA双链断裂（DSB）。两个不同S区之间的DSB形成突触，然后通过末端连接连接。DSB作为CSR的强制性中间体;然而，DSB也是细胞中可能发生的毒性最大的病变之一。单个未修复的DSB可能导致细胞死亡或参与染色体易位，这是许多类型癌症的标志，包括淋巴瘤。因此，CSR不仅需要DSB的产生，还需要DSB的有效修复。在这个建议中，我们测试的假设，即磷酸化的AID中起着至关重要的作用，产生DSBs。我们还探讨了DNA损伤传感器ATM参与诱导AID磷酸化和DSB修复过程中的假设。受损的CSR导致对病原体的反应能力受损，而异常的CSR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细胞淋巴瘤发生产生重大影响。

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.