Abstract
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.
Highlights
Cyclin-dependent kinases (CDKs) play key roles in cell cycle regulation
We were able to detect bouquets in 76% of WT spermatocytes but none in RingoA KO (Fig. 8e). These results indicate RingoA KO meiotic telomeres are essentially nonfunctional with reduced length, impaired chromatin compaction and largely unable to attach to the nuclear envelope (NE), as it has been reported in Cdk[2] KO spermatocytes[37]
RingoA or Cdk[2] KO spermatocytes are arrested in a pachytene-like stage and show non-homologous pairing with partner switching and telomere attachment failure, double-strand breaks (DSBs) repair block and sex-body absence
Summary
Cyclin-dependent kinases (CDKs) play key roles in cell cycle regulation. Genetic analysis in mice has revealed an essential role for Cdk[2] in meiosis, which renders Cdk[2] knockout (KO) mice sterile. Our results identify RingoA as an important activator of Cdk[2] at meiotic telomeres, and provide genetic evidence for a physiological function of mammalian Cdk[2] that is not dependent on cyclins. XRINGO-activated Cdk[1] and Cdk[2] have altered substrate specificity and can phosphorylate the CDK inhibitory kinase Myt[1] on three specific Ser residues much more efficiently than the cyclin-activated CDKs6 These phosphorylations inhibit the catalytic activity of Myt[1], which probably accounts for the role of XRINGO in Xenopus oocyte maturation[6,7,8]. We provide evidence that Cdk2-RingoA regulates the inner nuclear membrane protein Sun[1] for meiotic telomere tethering to the nuclear envelope (NE), a prerequisite for chromosome pairing and successful completion of the first meiotic prophase
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