活化诱导胞嘧啶脱氨酶（AID）对抗体多样性尤为重要。AID蛋白能够将抗体基因上的胞嘧啶通过脱氨基作用变为尿嘧啶，从而诱发体细胞高频突变和类别转换重组。AID作为脱氨酶还能够在B细胞基因组上的一些特殊位点产生脱靶效应，导致基因组突变和染色体易位。我们最新的数据表明，AID作为胞质蛋白，仅在细胞周期的G1早期短暂停留在细胞核中，其脱氨基作用也被限制在这一时间窗口中。在本项目中，我们计划研究AID蛋白在B细胞G1早期时间窗口中诱导抗体多样性的调控机制。我们将深入研究AID在G1早期短暂停留在核内的分子机制，探索AID诱导产生的尿嘧啶的定位特征，观测抗体基因的亚细胞定位及动态变化，寻找AID在G1早期的相互作用蛋白，并力图揭示AID对抗体基因特异靶向性的分子调控机理。本项目的实施不仅可以加深我们理解AID诱导抗体多样性的时空调节机制，还能促进我们在B细胞中探索被限制在G1早期的DNA损伤机制。

Activation-induced cytidine deaminase (AID) is the key protein for antibody diversification and efficient humoral immune response. It converts cytosine into uracil at immunoglobulin genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR). In addition, this enzyme produces DNA lesions at off-target sites throughout genome, leading to mutations and chromosome translocations. However, AID is mostly cytoplasmic, and how and exactly when it accesses nuclear DNA remains enigmatic. Our very recent data suggested that AID exploits an early G1-restricted DNA damage mechanism, transiently staying in the nucleus after cell division, to generate deamination. In this proposed project, we will investigate the regulation mechanism of AID-induced antibody diversification during the early G1 time window in B lymphocytes. We plan to unveil the molecular mechanism for AID's nuclear localization after cell division, explore the localization of the AID-induced uracils on the immunoglobulin gene IgH, observe the subcellular localization of IgH in the daughter cells, identify AID's early G1-specific interacting proteins, and try to explain why AID mainly deaminates the immunoglobulin genes. This project will not only improve our understanding about the spatial and temporal regulation of AID-induced deamination in B lymphocytes, but also unravel the mystery of the early G1-restricted DNA damage mechanism.