Essential role of the Cdk2 activator RingoA in meiotic telomere tethering to the nuclear envelope

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.

New insights into Cdk2 regulation during meiosis

“…The arrested germ cells then undergo apoptosis probably due to the pachytene checkpoint, which is activated by the accumulation of unrepaired DNA. 4 RingoA localizes to the telomeric regions in pachytene spermatocytes, as it has been reported for Cdk2, 5 co-localizes with Cdk2 from the leptotene stage and then disappears from telomeres as cells enter the diplotene stage. RingoA and Cdk2 also co-localize along the asynapsed sex chromosome arms in pachytene spermatocytes.…”

“…RingoA-deficient spermatocytes show decreased levels of the histone H3 trimethylated at Lys9 (H3K9-3me), whereas the amount of the histone H3 trimethylated at Lys4 (H3K4-3me) is increased. 4 Reduction of H3K9-me3 is thought to cause telomere shortening, which is actually observed in RingoA-deficient spermatocytes. 4 Moreover, aberrant chromosome methylation has been associated with non-homologous meiotic chromosome pairing, 7 and might be also related to the telomere fusion and nonhomologous chromosome pairing that are observed in RingoAdeficient germ cells.…”

“…4 Reduction of H3K9-me3 is thought to cause telomere shortening, which is actually observed in RingoA-deficient spermatocytes. 4 Moreover, aberrant chromosome methylation has been associated with non-homologous meiotic chromosome pairing, 7 and might be also related to the telomere fusion and nonhomologous chromosome pairing that are observed in RingoAdeficient germ cells. How RingoA could modulate histone H3 methylation during meiosis remains unclear, but it is interesting to speculate that histone H3 phosphorylation by RingoACdk2 could be involved.…”

“…However, they are sterile and have hypoplastic testes and ovaries, supporting an important role for RingoA in mammalian meiotic progression. 4 Importantly, spermatocytes and oocytes that are deficient in RingoA show identical phenotypes as those deficient in Cdk2, 5 namely they are mostly arrested in a pachytene-like stage of prophase I with non-homologous chromosome pairing, telomere detachment from the inner nuclear membrane (INM) and telomere fusion (Fig. 1).…”

“…Interestingly, RingoA-deficient spermatocytes show impaired localization to telomeres of Sun1, a protein required for telomere tethering to the INM, whereas the telomeric localization of TERB1, another protein required for telomere-INM tethering, is maintained. 4 RingoA-Cdk2 can phosphorylate in vitro the Nterminus of Sun1, which is the domain involved in binding to TERB1, so it is possible that RingoA-Cdk2 regulates the tethering of telomeres to the INM through phosphorylation of Sun1, but the detailed physiological mechanism remains unclear. In contrast to the co-localization of RingoA and Cdk2 in telomeres and sex chromosomes, RingoA does not co-localize with Cdk2 at crossing-over sites.…”