Posttranslational Control of Cdc25 Degradation Terminates Drosophila's Early Cell-Cycle Program

Howard Hughes Medical Institute, Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Current biology: CB (Impact Factor: 9.57). 12/2012; 23(2). DOI: 10.1016/j.cub.2012.11.029
Source: PubMed


In most metazoans, early embryonic development is characterized by rapid mitotic divisions that are controlled by maternal mRNAs and proteins that accumulate during oogenesis [1]. These rapid divisions pause at the midblastula transition (MBT), coinciding with a dramatic increase in gene transcription and the degradation of a subset of maternal mRNAs [2, 3]. In Drosophila, the cell-cycle pause is controlled by inhibitory phosphorylation of Cdk1, which in turn is driven by downregulation of the activating Cdc25 phosphatases [4, 5]. Here, we show that the two Drosophila Cdc25 homologs, String and Twine, differ in their dynamics and that, contrary to current models [4], their downregulations are not controlled by mRNA degradation but through different posttranslational mechanisms. The degradation rate of String protein gradually increases during the late syncytial cycles in a manner dependent on the nuclear-to-cytoplasmic ratio and on the DNA replication checkpoints. Twine, on the other hand, is targeted for degradation at the onset of the MBT through a switch-like mechanism controlled, like String, by the nuclear-to-cytoplasmic ratio, but not requiring the DNA replication checkpoints. We demonstrate that posttranslational control of Twine degradation ensures that the proper number of mitoses precede the MBT.

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    • "However, at present it is not clear what role the nucleus to cytoplasm ratio plays in regulating the cell cycle changes in Drosophila. The studies by the Wieschaus and O'Farrell groups indicate that the nucleus to cytoplasm ratio triggers the onset of transcription of the genes required for Twine destruction (Di Talia et al., 2013; Farrell and O'Farrell, 2013). The study by the Großhans group, however, suggests that the destruction of Twine occurs independently of changes to the nucleus to cytoplasm ratio (Sung et al., 2013). "
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    ABSTRACT: The initial phases of embryonic development occur in the absence of de novo transcription and are instead controlled by maternally inherited mRNAs and proteins. During this initial period, cell cycles are synchronous and lack gap phases. Following this period of transcriptional silence, zygotic transcription begins, the maternal influence on development starts to decrease, and dramatic changes to the cell cycle take place. Here, we discuss recent work that is shedding light on the maternal to zygotic transition and the interrelated but distinct mechanisms regulating the onset of zygotic transcription and changes to the cell cycle during early embryonic development.
    Full-text · Article · Oct 2014 · Development
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    ABSTRACT: Three recent studies revise the prevailing view of regulation of the mid-blastula transition in Drosophila, indicating particular requirements for the Cdc25 phosphatase Twine and for zygotic transcription of a specific set of genes.
    Full-text · Article · Jan 2013 · Current biology: CB
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    ABSTRACT: The nucleus to cytoplasm (N/C) ratio controls S phase dynamics in many biological systems, most notably the abrupt remodeling of the cell cycle that occurs at the midblastula transition (MBT) in early Xenopus laevis embryos. After an initial series of rapid cleavage cycles consisting only of S and M phases, a critical N/C ratio is reached which causes a sharp increase in the length of S phase as the cell cycle is reconfigured to resemble somatic cell cycles. How the N/C ratio determines the length of S phase has been a long-standing problem in developmental biology. Using Xenopus egg extracts, we show that DNA replication at high N/C ratio is restricted by one or more limiting substances. We report here that the protein phosphatase PP2A, in conjunction with its B55α regulatory subunit, becomes limiting for replication origin firing at high N/C ratio, and this in turn leads to reduced origin activation and an increase in the time required to complete S phase. Increasing the levels of PP2A catalytic subunit or B55α experimentally restores rapid DNA synthesis at high N/C ratio. Inversely, reduction of PP2A or B55α levels sharply extends S phase even in low N/C extracts. These results identify PP2A-B55α as a link between DNA replication and N/C ratio in egg extracts and suggest a mechanism that may influence the onset of the MBT in vivo.
    No preview · Article · Aug 2013 · Journal of Biological Chemistry
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