Mechanistic Elucidation of Class Switch Recombination and Somatic Hypermutation

摘要 当遇到抗原时，成熟的B细胞表达活化诱导的胞苷脱氨酶(AID)并经历 免疫球蛋白重链(IGH)、类开关重组(CSR)和体细胞高突变(SHM)。企业社会责任 通过预定的DNA双链断裂(DSB)的产生，这构成了 大多数毒性损伤可能发生在细胞中。单个未修复的DSB可能导致细胞死亡或增强 染色体易位是包括淋巴瘤在内的许多类型癌症的特征。因此， 促进DSB产生和促进DSB修复的机制与免疫和 保持基因组的完整性。在这个方案中，我们测试了单个蛋白质可以协调两种蛋白质的概念 DSB的形成和中介末端连接，以有效地产生和修复DSB。我们检验了这一假设 核小体重塑蛋白CHD4协调IgH DSB的生成和修复(AIM 1)和C- AID末端介导IgH双链断裂的有效DNA修复(目标2)。实验圆满完成 对我们理解B细胞免疫和B细胞淋巴瘤都有深远的影响。

ABSTRACT Upon encountering antigens, mature B cells express activation induced cytidine deaminase (AID) and undergo immunoglobulin heavy chain (Igh) class switch recombination (CSR) and somatic hypermutation (SHM). CSR proceeds through the obligate generation of DNA double strand breaks (DSBs), which constitute one of the most toxic lesions that can occur in a cell. A single unrepaired DSB can cause cell death or potentiate chromosomal translocations that are hallmarks of many types of cancer, including lymphomas. Thus, mechanisms that promote generation of DSBs and facilitate DSB repair are intergral to both immunity and preservation of genomic integrity. In this proposal we test the notion that single proteins can coordinate both DSB formation and mediate end-joining to efficiently generate and repair DSBs. We test the hypothesis that the nucleosomal remodeling protein CHD4 co-ordinates generation and repair of Igh DSBs (aim 1) and the C- terminus of AID mediates efficient DNA repair of Igh DSBs (aim 2). Successful completion of the experiments will have far reaching implications in our understanding of both B cell immunity and B cell lymphomas.