生精障碍新致病基因SHOC1在人精母细胞减数分裂中的作用及机制研究

减数分裂是精子发生的关键阶段，其异常会导致生精障碍。DNA交叉形成和联会复合体组装是精母细胞减数分裂中的关键事件，而ZZS蛋白复合物是调控这两个事件的重要组件。申请人前期发现两个无精子症家系存在SHOC1（人ZZS蛋白复合物之一）双等位功能缺失突变，国内外未见报道。证实SHOC1突变导致精子发生停滞于第一次减数分裂前期偶线期，提示SHOC1对人减数分裂至关重要。但SHOC1如何结合C1orf146和TEX11形成人ZZS蛋白复合物，如何调控人精母细胞减数分裂DNA交叉形成和联会复合体组装机制鲜有报道。本项目旨在明确SHOC1在人睾丸组织及精母细胞特异表达特征，剖析SHOC1-C1orf146复合体特异结合DNA结构进而调控DNA交叉形成机理，阐释SHOC1与TEX11相互作用调控联会复合体组装机制。本研究将为阐明人精母细胞减数分裂分子机制提供重要理论依据，为治疗生精障碍提供新分子靶标。

Meiosis is a complex process in spermatogenesis, while meiotic abnormalities could lead to spermatogenic failure. Meiosis consists of two key events, including DNA crossover (CO) formation and synaptonemal complex (SC) assembly. The ZZS protein complex plays essential roles in these two key events. In the previous research, we found biallelic Loss-of-Function (LoF) mutations of SHOC1 (part of the ZZS protein complex) in two azoospermia pedigrees. And the spermatogenesis of all male patients arrested at zygotene stage (Prophase, Meiosis I), suggesting that SHOC1 might play a crucial role in human meiosis. However, the formation of the human ZZS protein complex (SHOC1/C1orf146/TEX11) and mechanism of SHOC1 in CO formation and SC assembly of human meiosis remain unclear. In the current project, the following studies will be carried out: 1) Identification of SHOC1 in meiotic germ cells of human spermatogenesis; 2) Exploration on the mechanism of SHOC1-C1orf146 complex in promoting CO formation; 3) Elucidation of interaction between SHOC1 and TEX11, and how SHOC1-TEX11 complex regulates SC assembly. This study will provide an important theoretical basis for elucidating the molecular mechanism of human meiosis and provide new targets for the management of spermatogenic failure.