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

Abstract

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 Mid-Blastula 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 homologues, String and Twine, differ in their dynamics and that, contrary to current models [4], their down-regulations are not controlled by mRNA degradation but through different post-translational 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 post-translational control of Twine degradation ensures that the proper number of mitoses precede the MBT