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

SummaryIn 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 and 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 and 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.

► String and Twine are controlled by different posttranslational mechanisms
► DNA replication checkpoints control String, but not Twine, levels
► Switch-like degradation of Twine at the MBT is required for the cell-cycle pause
► The instability of String and Twine is transient