RNA-directed targeting of AID in immunity and cancer

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。在这个提议中，我们测试了非规范DNA结构 当G-四链体在CSR期间靶向DNA脱氨酶AID到染色质时(目标1)，AID可以 调节非免疫球蛋白基因的表达以影响B细胞反应(目标2)。圆满完成 实验将对我们理解B细胞免疫和B细胞产生深远的影响 淋巴瘤。

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 non-canonical DNA structures such as G-quadruplexes target the DNA deaminase AID to the chromatin during CSR (aim 1) and that AID can regulate expression of non-Ig genes to influence B cell responses (aim 2). Successful completion of the experiments will have far reaching implications in our understanding of both B cell immunity and B cell lymphomas.