Essential role of the Cdk2 activator RingoA in meiotic telomere tethering to the nuclear envelope.
Essential role of the Cdk2 activator RingoA in meiotic telomere tethering to the nuclear envelope.
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DOI：
10.1038/ncomms11084
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发表时间：
2016-03-30
影响因子：
16.6
通讯作者：
Nebreda AR
中科院分区：
文献类型：
--
作者：
Mikolcevic P;Isoda M;Shibuya H;del Barco Barrantes I;Igea A;Suja JA;Shackleton S;Watanabe Y;Nebreda AR
细胞周期蛋白依赖性激酶 (CDK) 在细胞周期调节中发挥关键作用。小鼠遗传分析揭示了 Cdk2 在减数分裂中的重要作用，这使得 Cdk2 敲除 (KO) 小鼠不育。在这里，我们发现，RingoA（一种 Cdk1 和 Cdk2 的非典型激活剂，与细胞周期蛋白没有氨基酸序列同源性）缺陷的小鼠是不育的，并且表现出与 Cdk2 KO 小鼠中观察到的减数分裂缺陷几乎相同的缺陷，包括非同源染色体配对、未修复的双链断裂、无法检测到的性体和粗线期停滞。有趣的是，RingoA 是 Cdk2 靶向端粒所必需的，而 RingoA KO 精母细胞显示端粒束缚受到严重影响，并且 Sun1 的分布受损，Sun1 是端粒附着到核膜上所必需的蛋白质。我们的结果确定 RingoA 是减数分裂端粒处 Cdk2 的重要激活剂，并为哺乳动物 Cdk2 不依赖于细胞周期蛋白的生理功能提供了遗传证据。 CDK 在细胞周期调节中发挥核心作用，通常由细胞周期蛋白激活。在这里，作者表明，RingoA 在减数分裂端粒处诱导 CDK2 的细胞周期蛋白独立功能，从而调节它们与核膜的束缚以及同源染色体的正确突触。
Cyclin-dependent kinases (CDKs) play key roles in cell cycle regulation. Genetic analysis in mice has revealed an essential role for Cdk2 in meiosis, which renders Cdk2 knockout (KO) mice sterile. Here we show that mice deficient in RingoA, an atypical activator of Cdk1 and Cdk2 that has no amino acid sequence homology to cyclins, are sterile and display meiotic defects virtually identical to those observed in Cdk2 KO mice including non-homologous chromosome pairing, unrepaired double-strand breaks, undetectable sex-body and pachytene arrest. Interestingly, RingoA is required for Cdk2 targeting to telomeres and RingoA KO spermatocytes display severely affected telomere tethering as well as impaired distribution of Sun1, a protein essential for the attachment of telomeres to the nuclear envelope. Our results identify RingoA as an important activator of Cdk2 at meiotic telomeres, and provide genetic evidence for a physiological function of mammalian Cdk2 that is not dependent on cyclins. CDKs play central roles in cell cycle regulation and are normally activated by cyclins. Here the authors show that RingoA induces a cyclin-independent function of CDK2 at meiotic telomeres, which regulates their tethering to the nuclear envelope and proper synapsis of homologous chromosomes.