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General Comment |
In yeasts, Cdc6 (Saccharomyces cerevisiae) and Cdc18 (Schizosaccharomyces pombe) associate with the origin recognition complex (ORC) proteins to render cells competent for DNA replication. Thus, Cdc6 has a critical regulatory role in the initiation of DNA replication in yeast.
NCBI Summary:
The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Cdc6, a protein essential for the initiation of DNA replication. This protein functions as a regulator at the early steps of DNA replication. It localizes in cell nucleus during cell cyle G1, but translocates to the cytoplasm at the start of S phase. The subcellular translocation of this protein during cell cyle is regulated through its phosphorylation by Cdks. Transcription of this protein was reported to be regulated in response to mitogenic signals through transcriptional control mechanism involving E2F proteins. [provided by RefSeq, Jul 2008]
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Comment |
Role of Cdc6 During Oogenesis and Early Embryo Development in Mouse and Xenopus laevis. [Borsuk E et al. (2017)$28247050] Cdc6 is an important player in cell cycle regulation. It is involved in the regulation of both S-phase and M-phase. Its role during oogenesis is crucial for repression of the S-phase between the first and the second meiotic M-phases, and it also regulates, via CDK1 inhibition, the M-phase entry and exit. This is of special importance for the reactivation of the major M-phase-regulating kinase CDK1 (Cyclin-Dependent Kinase 1) in oocytes entering metaphase II of meiosis and in embryo cleavage divisions, in which precise timing allows coordination between cell cycle events and developmental program of the embryo. In this chapter, we discuss the role of Cdc6 protein in oocytes and early embryos.//////////////////
Fine-tuning of Cdc6 accumulation by Cdk1 and MAP kinase is essential for completion of oocyte meiotic divisions. [Daldello EM et al. (2015)$26092930] Vertebrate oocytes proceed through the 1(st) and the 2(nd) meiotic division without intervening S-phase to become haploid. Although DNA replication does not take place, unfertilized oocytes acquire the competence to replicate DNA one hour after the 1(st) meiotic division, by accumulating an essential factor of the replicative machinery, Cdc6. Here, we discovered that the turnover of Cdc6 is precisely regulated in oocytes to avoid inhibition of Cdk1. At meiosis resumption, Cdc6 starts to be expressed but cannot accumulate due to a degradation mechanism activated through Cdk1. During transition from 1(st) to 2(nd) meiotic division, Cdc6 is under antagonistic regulation of Cyclin B, whose interaction with Cdc6 stabilizes the protein, and Mos/MAPK that negatively controls its accumulation. Since overexpressing Cdc6 inhibits Cdk1 reactivation and drives oocytes into a replicative interphasic state, the fine-tuning of Cdc6 accumulation is essential to ensure two meiotic waves of Cdk1 activation and to avoid unscheduled DNA replication during meiotic maturation.//////////////////
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Whitmire E, et al reported that Cdc6 synthesis regulates replication competence in Xenopus oocytes.
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The early division cycles of an embryo rely on the oocyte's ability to replicate DNA. During meiosis, oocytes temporarily lose this ability. After a single round of pre-meiotic S-phase, oocytes enter meiosis and rapidly arrest at prophase of meiosis I (G2). Upon hormonal stimulation, arrested oocytes resume meiosis, re-establish DNA replication competence in meiosis I shortly after germinal vesicle breakdown (GVBD), but repress replication until fertilization. How oocytes lose and regain replication competence during meiosis are important questions underlying the production of functional gametes. Here we show that the inability of immature Xenopus oocytes to replicate is linked to the absence of the Cdc6 protein and the cytoplasmic localization of other initiation proteins. Injection of Cdc6 protein into immature oocytes does not induce DNA replication. However, injection of Cdc6 into oocytes undergoing GVBD is sufficient to induce DNA replication in the absence of protein synthesis. Results show that GVBD and Cdc6 synthesis are the only events that limit the establishment of the oocyte's replication competence during meiosis.
Lemaitre JM, et al 2002 reported that competence to replicate in the unfertilized egg is conferred by Cdc6 during meiotic maturation.
Meiotic maturation, the final step of oogenesis, is a crucial stage of development in which an immature oocyte becomes a fertilizable egg. In Xenopus, the ability to replicate DNA is acquired during maturation at breakdown of the nuclear envelope by translation of a DNA synthesis inducer that is not present in the oocyte. Here we identify Cdc6, which is essential for recruiting the minichromosome maintenance (MCM) helicase to the pre-replication complex, as this inducer of DNA synthesis. We show that maternal cdc6 mRNA but not protein is stored in the oocyte. Cdc6 protein is synthesized during maturation, but this process can be blocked by degrading the maternal cdc6 mRNA by oligonucleotide antisense injections or by translation inhibition. Rescue experiments using recombinant Cdc6 protein show that Cdc6 is the only missing replication factor whose translation is necessary and sufficient to confer DNA replication competence to the egg before fertilization. The licence to replicate is given by Cdc6 at the end of meiosis I, but the cytostatic factor (CSF) pathway, which maintains large amounts of active Cdc2/Cyclin B2, prevents the entry into S phase until fertilization.
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