Tu Zhaowei, Bayazit Mustafa Bilal, Liu Hongbin, Zhang Jingjing, Busayavalasa Kiran, Risal Sanjiv, Shao Jingchen, Satyanarayana Ande, Coppola Vincenzo, Tessarollo Lino, Singh Meenakshi, Zheng Chunwei, Han Chunsheng, Chen Zijiang, Kaldis Philipp, Gustafsson Jan-Åke, Liu Kui
Department of Chemistry and Molecular Biology, University of Gothenburg, SE-40530 Gothenburg, Sweden.
The Key Laboratory of Reproductive Endocrinology, Shandong University, Ministry of Education, Jinan 250001, China.
Proc Natl Acad Sci U S A. 2017 Jan 17;114(3):592-597. doi: 10.1073/pnas.1618465114. Epub 2016 Dec 28.
Telomere attachment to the nuclear envelope (NE) is a prerequisite for chromosome movement during meiotic prophase I that is required for pairing of homologous chromosomes, synapsis, and homologous recombination. Here we show that Speedy A, a noncanonical activator of cyclin-dependent kinases (Cdks), is specifically localized to telomeres in prophase I male and female germ cells in mice, and plays an essential role in the telomere-NE attachment. Deletion of Spdya in mice disrupts telomere-NE attachment, and this impairs homologous pairing and synapsis and leads to zygotene arrest in male and female germ cells. In addition, we have identified a telomere localization domain on Speedy A covering the distal N terminus and the Cdk2-binding Ringo domain, and this domain is essential for the localization of Speedy A to telomeres. Furthermore, we found that the binding of Cdk2 to Speedy A is indispensable for Cdk2's localization on telomeres, suggesting that Speedy A and Cdk2 might be the initial components that are recruited to the NE for forming the meiotic telomere complex. However, Speedy A-Cdk2-mediated telomere-NE attachment is independent of Cdk2 activation. Our results thus indicate that Speedy A and Cdk2 might mediate the initial telomere-NE attachment for the efficient assembly of the telomere complex that is essential for meiotic prophase I progression.
端粒与核膜（NE）的附着是减数分裂前期I染色体运动的前提条件，而染色体运动是同源染色体配对、联会和同源重组所必需的。在此，我们表明，细胞周期蛋白依赖性激酶（Cdks）的非典型激活剂Speedy A特异性定位于小鼠雄性和雌性生殖细胞减数分裂前期I的端粒，并在端粒与核膜的附着中起关键作用。小鼠中Spdya的缺失破坏了端粒与核膜的附着，这损害了同源配对和联会，并导致雄性和雌性生殖细胞在偶线期停滞。此外，我们在Speedy A上鉴定出一个端粒定位结构域，该结构域覆盖远端N端和与Cdk2结合的Ringo结构域，且该结构域对于Speedy A定位于端粒至关重要。此外，我们发现Cdk2与Speedy A的结合对于Cdk2定位于端粒是不可或缺的，这表明Speedy A和Cdk2可能是被招募到核膜以形成减数分裂端粒复合体的初始成分。然而，Speedy A-Cdk2介导的端粒与核膜的附着独立于Cdk2的激活。因此，我们的结果表明，Speedy A和Cdk2可能介导了端粒与核膜的初始附着，以有效地组装对减数分裂前期I进程至关重要的端粒复合体。
