In several species, including Xenopus, mouse and human, two members of cyclin A family were identified. Cyclin A2, which is ubiquitously expressed in dividing cells and plays role in DNA replication, entry into mitosis and spindle assembly, and cyclin A1, whose function is less clear and which is expressed in spermatocytes, leukemia cells and in postmitotic multiciliated cells. Deletion of the gene showed that cyclin A1 is essential for male meiosis, but nonessential for female meiosis. Our results revealed, that the cyclin A1 is not only dispensable in oocytes, we show here that its expression is in fact undesirable in these cells. Our data demonstrate that the APC/C and proteasome in oocytes are unable to target sufficiently cyclin A1 before anaphase, which leads into anaphase arrest and direct inhibition of separase. The cyclin A1-induced cell cycle arrest is oocyte-specific and the presence of cyclin A1 in early embryos has no effect on cell cycle progression or chromosome division. Cyclin A1 is therefore not only an important cell cycle regulator with biased expression in germline, being essential for male and damaging for female meiosis, its persistent expression during anaphase in oocytes shows fundamental differences between APC/C function in oocytes and in early embryos.

Central European Institute of Technology Department of Genetics and Reproduction Veterinary Research Institute Brno Czech Republic

Institute of Animal Physiology and Genetics Czech Academy of Sciences Libechov Czech Republic

Zobrazit více v PubMed

Evans T, Rosenthal ET, Youngblom J, Distel D, Hunt T. Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell. 1983;33:389–396. doi: 10.1016/0092-8674(83)90420-8. PubMed DOI

Satyanarayana A, Kaldis P. Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms. Oncogene. 2009;28:2925–2939. doi: 10.1038/onc.2009.170. PubMed DOI

Howe JA, Howell M, Hunt T, Newport JW. Identification of a developmental timer regulating the stability of embryonic cyclin A and a new somatic A-type cyclin at gastrulation. Genes. Dev. 1995;9:1164–1176. doi: 10.1101/gad.9.10.1164. PubMed DOI

Sweeney C, et al. A distinct cyclin A is expressed in germ cells in the mouse. Development. 1996;122:53–64. PubMed

Yang R, Morosetti R, Koeffler HP. Characterization of a second human cyclin A that is highly expressed in testis and in several leukemic cell lines. Cancer Res. 1997;57:913–920. PubMed

Krämer A, et al. Cyclin A1 is predominantly expressed in hematological malignancies with myeloid differentiation. Leukemia. 1998;12:893–898. doi: 10.1038/sj.leu.2401051. PubMed DOI

van der Meer T, et al. Cyclin A1 protein shows haplo-insufficiency for normal fertility in male mice. Reproduction. 2004;127:503–511. doi: 10.1530/rep.1.00131. PubMed DOI

Joshi AR, Jobanputra V, Lele KM, Wolgemuth DJ. Distinct properties of cyclin-dependent kinase complexes containing cyclin A1 and cyclin A2. Biochem. Biophys. Res. Commun. 2009;378:595–599. doi: 10.1016/j.bbrc.2008.11.077. PubMed DOI PMC

Diederichs S, et al. Identification of interaction partners and substrates of the cyclin A1-CDK2 complex. J. Biol. Chem. 2004;279:33727–33741. doi: 10.1074/jbc.M401708200. PubMed DOI

Müller-Tidow C, et al. The cyclin A1-CDK2 complex regulates DNA double-strand break repair. Mol. Cell Biol. 2004;24:8917–8928. doi: 10.1128/MCB.24.20.8917-8928.2004. PubMed DOI PMC

Vladar, E. K. et al. Cyclin-dependent kinase control of motile ciliogenesis. Elife7, (2018). PubMed PMC

Liu D, et al. Cyclin A1 is required for meiosis in the male mouse. Nat. Genet. 1998;20:377–380. doi: 10.1038/3855. PubMed DOI

Lele KM, Wolgemuth DJ. Distinct regions of the mouse cyclin A1 gene, Ccna1, confer male germ-cell specific expression and enhancer function. Biol. Reprod. 2004;71:1340–1347. doi: 10.1095/biolreprod.104.030387. PubMed DOI

Ravnik SE, Wolgemuth DJ. Regulation of meiosis during mammalian spermatogenesis: the A-type cyclins and their associated cyclin-dependent kinases are differentially expressed in the germ-cell lineage. Dev. Biol. 1999;207:408–418. doi: 10.1006/dbio.1998.9156. PubMed DOI

Wolgemuth DJ, Manterola M, Vasileva A. Role of cyclins in controlling progression of mammalian spermatogenesis. Int. J. Dev. Biol. 2013;57:159–168. doi: 10.1387/ijdb.130047av. PubMed DOI PMC

Ortega S, et al. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat. Genet. 2003;35:25–31. doi: 10.1038/ng1232. PubMed DOI

Nickerson HD, Joshi A, Wolgemuth DJ. Cyclin A1-deficient mice lack histone H3 serine 10 phosphorylation and exhibit altered aurora B dynamics in late prophase of male meiosis. Dev. Biol. 2007;306:725–735. doi: 10.1016/j.ydbio.2007.04.009. PubMed DOI PMC

Liu D, Liao C, Wolgemuth DJ. A role for cyclin A1 in the activation of MPF and G2-M transition during meiosis of male germ cells in mice. Dev. Biol. 2000;224:388–400. doi: 10.1006/dbio.2000.9776. PubMed DOI

Fuchimoto D, Mizukoshi A, Schultz RM, Sakai S, Aoki F. Posttranscriptional regulation of cyclin A1 and cyclin A2 during mouse oocyte meiotic maturation and preimplantation development. Biol. Reprod. 2001;65:986–993. doi: 10.1095/biolreprod65.4.986. PubMed DOI

Persson JL, et al. Distinct roles for the mammalian A-type cyclins during oogenesis. Reproduction. 2005;130:411–422. doi: 10.1530/rep.1.00719. PubMed DOI

Li, J. et al. Cyclin B2 can compensate for Cyclin B1 in oocyte meiosis I. J Cell Biol (2018). PubMed PMC

Zhang, Q. H. et al. Cyclin A2 modulates kinetochore-microtubule attachment in meiosis II. J Cell Biol (2017). PubMed PMC

Jones KT. Turning it on and off: M-phase promoting factor during meiotic maturation and fertilization. Mol. Hum. Reprod. 2004;10:1–5. doi: 10.1093/molehr/gah009. PubMed DOI

Li, J., Qian, W. P. & Sun, Q. Y. Cyclins regulating oocyte meiotic cell cycle progression. Biol Reprod (2019). PubMed PMC

Homer HA, McDougall A, Levasseur M, Murdoch AP, Herbert M. Mad2 is required for inhibiting securin and cyclin B degradation following spindle depolymerisation in meiosis I mouse oocytes. Reproduction. 2005;130:829–843. doi: 10.1530/rep.1.00856. PubMed DOI

McGuinness BE, et al. Regulation of APC/C activity in oocytes by a Bub1-dependent spindle assembly checkpoint. Curr. Biol. 2009;19:369–380. doi: 10.1016/j.cub.2009.01.064. PubMed DOI

King RW, Glotzer M, Kirschner MW. Mutagenic analysis of the destruction signal of mitotic cyclins and structural characterization of ubiquitinated intermediates. Mol. Biol. Cell. 1996;7:1343–1357. doi: 10.1091/mbc.7.9.1343. PubMed DOI PMC

Kobayashi H, et al. Identification of the domains in cyclin A required for binding to, and activation of, p34cdc2 and p32cdk2 protein kinase subunits. Mol. Biol. Cell. 1992;3:1279–1294. doi: 10.1091/mbc.3.11.1279. PubMed DOI PMC

Sørensen CS, et al. A conserved cyclin-binding domain determines functional interplay between anaphase-promoting complex-Cdh1 and cyclin A-Cdk2 during cell cycle progression. Mol. Cell Biol. 2001;21:3692–3703. doi: 10.1128/MCB.21.11.3692-3703.2001. PubMed DOI PMC

Luca FC, Shibuya EK, Dohrmann CE, Ruderman JV. Both cyclin A delta 60 and B delta 97 are stable and arrest cells in M-phase, but only cyclin B delta 97 turns on cyclin destruction. EMBO J. 1991;10:4311–4320. doi: 10.1002/j.1460-2075.1991.tb05009.x. PubMed DOI PMC

Kudo NR, et al. Resolution of chiasmata in oocytes requires separase-mediated proteolysis. Cell. 2006;126:135–146. doi: 10.1016/j.cell.2006.05.033. PubMed DOI

Stemmann O, Zou H, Gerber SA, Gygi SP, Kirschner MW. Dual inhibition of sister chromatid separation at metaphase. Cell. 2001;107:715–726. doi: 10.1016/S0092-8674(01)00603-1. PubMed DOI

Huang X, et al. Inhibitory phosphorylation of separase is essential for genome stability and viability of murine embryonic germ cells. PLoS Biol. 2008;6:e15. doi: 10.1371/journal.pbio.0060015. PubMed DOI PMC

Schultz R. Regulation of zygotic gene activation in the mouse. BioEssays: N. Rev. molecular, Cell. developmental Biol. 1993;15:531–538. doi: 10.1002/bies.950150806. PubMed DOI

Roy A, Matzuk MM. Deconstructing mammalian reproduction: using knockouts to define fertility pathways. Reproduction. 2006;131:207–219. doi: 10.1530/rep.1.00530. PubMed DOI

Matzuk MM, Lamb DJ. Genetic dissection of mammalian fertility pathways. Nat. Cell Biol. 2002;4(Suppl):s41–9. PubMed

Lindholm A, Sutter A, Künzel S, Tautz D, Rehrauer H. Effects of a male meiotic driver on male and female transcriptomes in the house mouse. Proc. Biol. Sci. 2019;286:20191927. doi: 10.1098/rspb.2019.1927. PubMed DOI PMC

Piprek RP, Damulewicz M, Tassan JP, Kloc M, Kubiak JZ. Transcriptome profiling reveals male- and female-specific gene expression pattern and novel gene candidates for the control of sex determination and gonad development in Xenopus laevis. Dev. Genes. Evol. 2019;229:53–72. doi: 10.1007/s00427-019-00630-y. PubMed DOI PMC

Li, J., Dong, F., Ouyang, Y. C., Sun, Q. Y. & Qian, W. P. Overexpression of cyclin A1 promotes meiotic resumption but induces premature chromosome separation in mouse oocyte. J Cell Physiol (2020). PubMed

Chaigne A, et al. A soft cortex is essential for asymmetric spindle positioning in mouse oocytes. Nat. Cell Biol. 2013;15:958–966. doi: 10.1038/ncb2799. PubMed DOI

Petronczki M, Siomos MF, Nasmyth K. Un ménage à quatre: the molecular biology of chromosome segregation in meiosis. Cell. 2003;112:423–440. doi: 10.1016/S0092-8674(03)00083-7. PubMed DOI

Kudo NR, et al. Role of cleavage by separase of the Rec8 kleisin subunit of cohesin during mammalian meiosis I. J. Cell Sci. 2009;122:2686–2698. doi: 10.1242/jcs.035287. PubMed DOI PMC

Gorr IH, Boos D, Stemmann O. Mutual inhibition of separase and Cdk1 by two-step complex formation. Mol. Cell. 2005;19:135–141. doi: 10.1016/j.molcel.2005.05.022. PubMed DOI

Santamaría D, et al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature. 2007;448:811–815. doi: 10.1038/nature06046. PubMed DOI

Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P. Cdk2 Knockout Mice Are Viable. Curr. Biol. 2003;13:1775–1785. doi: 10.1016/j.cub.2003.09.024. PubMed DOI

Separase and Roads to Disengage Sister Chromatids during Anaphase

Accumulation of Securin on Spindle During Female Meiosis I