激活诱导胞嘧啶脱氨酶（AID）介导抗体类别转换（CSR），是B细胞产生多样性抗体的关键因子。AID被激酶磷酸化，在众多辅因子调控下，介导Ig基因Switch区双链断裂。申请人通过表型筛选，鉴定得到影响CSR的新因子激酶锚定蛋白AKAP8。进一步实验显示，AKAP8促进CSR不依赖典型的激酶锚定作用，但与AID存在互作。通过AKAP8功能分析，发现其能够增强组蛋白修饰，与RNA代谢加工组分存在互作关系，并识别G-rich序列。据此推测：AKAP8可能特异性调控Switch区AID的招募，进而影响CSR。本课题拟采用系列技术手段，深入研究AKAP8在Switch区组蛋白修饰和R-loop等特征结构形成的作用，并解析AKAP8促进Switch区招募AID的分子基础，从多层面揭示AKAP8调节AID介导CSR关键过程的功能特点，同时为AID脱靶向诱发疾病的研究提供信息。

Activation-induced cytidine deaminase (AID) mediates class switch recombination (CSR) and plays key roles in producing multiple diversity of antibodies in B cells. With the helps from many cofactors of AID, phosphorylated AID by Protein kinase A (PKA) is recruited to the repetitive G-rich Switch region of immunoglobulin genes and mediates double-strand breaks. However, whether A-kinase anchor proteins (AKAP) members as a cofactor involve in CSR process has yet been studied. Through data analysis and RNAi screening, we identified that AKAP8 is a novel factor which promotes CSR. Further experiments suggested that CSR promotion by AKAP8 is independent of typical PKA anchoring and probable through its association with AID. Basing of functional analysis and interaction protein clustering, AKAP8 is found to enhance histone modification, recognize G-rich sequences, and interact with RNA processing components. It is reasonable to speculate that AKAP8 may specifically promote the recruitment of AID in the Switch region, which in turn enhances CSR. In this project, we design a serial of experiments to study in depth the effects of AKAP8 on the histone modification and formation of specific structures such as R-loop in the Switch region, and dissect the molecular basis of AID recruiting to Switch regions promoted by AKAP8. Finally, we aim to reveal the functional characteristics of AKAP8 in promoting AID mediated CSR and uncover the correlated mechanism from multiple aspects. The project will also benefit the studies on diseases induced by AID off-targeting.