哺乳动物减数分裂前期I Speedy A/CDK2调控端粒运动的分子机制

减数分裂是有性生殖的基础，该过程染色体的正确分离依赖于同源染色体的配对和联会。在减数分裂前期I端粒和核膜LINC复合物结合以带动染色体运动，促进同源染色体配对。哺乳动物基因敲除实验已经鉴定出包括Speedy A/CDK2复合物在内的一系列蛋白质参与调控端粒的核膜定位；然而这些蛋白质如何协同调控端粒-LINC复合物的结合及端粒的运动仍不清楚。我们前期工作表明端粒可通过TTM复合物定位到核膜，再在其它蛋白质的参与下结合到LINC复合物；Speedy A可分别与端粒和核膜组分发生作用。据此我们提出假说：Speedy A/CDK2通过修饰端粒和核膜特定组分调控端粒-LINC复合物的结合及端粒的运动。本项目将应用分子、生化、结构、遗传等方法，研究Speedy A/CDK2在减数分裂前期I发挥功能的结构基础和分子机制，探讨端粒及染色体的运动对同源染色体配对与联会的作用，为临床不育症病理研究提供新线索。

Meiosis is the basis of sexual reproduction, in which accurate segregation of chromosomes requires the homologs to pair and synapse. During meiotic prophase I, telomeres bind to the LINC complex on the nuclear envelope (NE) to drive chromosome movements and promoter homologous chromosome pairing. Gene knock-out experiments have identified several key proteins in mammals, including the Speedy A/CDK2 complex, involved in regulation of telomere-NE attachment. However, how these proteins cooperatively regulate telomere-LINC complex connection and telomere movements remains elusive. Our previous studies revealed that telomeres may attach to the NE via the TTM (TERB1-TERB2-MAJIN) complex and then bind to the LINC complex with the participation of additional proteins. Moreover, Speedy A interacts with telomeres and components on the NE. Accordingly, we speculate that Speedy A/CDK2 might regulate the telomere-LINC complex connection and telomere movements by modifying key proteins at telomeres or on the NE. By using molecular, biochemical, structural and genetic methods, this project will further study the structural basis and molecular mechanism of Speedy A/CDK2 functioning in meiotic prophase I, and reveal the important roles of telomere and chromosome movements in homologous pairing and synapsis, providing new clues for the pathological study of human infertility.