Developing S-phase control

Abstract

The duration of S phase in early embryos is often short, and then increases as development proceeds because of the appearance of late-replicating regions of the genome. In the April 1, 2012, issue of Genes & Development, Farrell and colleagues (pp. 714-725) demonstrate that the down-regulation of cyclin-dependent kinase 1 (Cdk1) activity triggers the onset of late-replicating DNA and an increase in S-phase length in Drosophila embryos, revealing an unexpected role for Cdk1 in replication control during development.

Figure 1.

Cdks are regulated by tyrosine phosphorylation and control pre-RC assembly and firing. Cdk activity plays opposing roles in controlling DNA replication at different times in the cell cycle, both inhibiting pre-RC assembly and triggering origin firing, leading to bidirectional replication fork movement. Cdk1 activity requires binding to cyclin and is regulated by the opposing activities of Cdc25 phosphatase and Wee1 kinase, which phosphorylates a tyrosine in the Cdk1 active site that inhibits ATP binding.

Figure 2.

Down-regulation of the mitotic kinase activator Cdc25 triggers the onset of late origin firing during S phase of early Drosophila development. The MBT in Drosophila embryos occurs between embryonic cycles 13 and 14 and is associated with the destruction of maternal Cdc25 mRNA and protein. Because of constitutive Wee1 kinase activity, the down-regulation of maternal Cdc25 leads to the accumulation of inactive Cyclin/Cdk1 complexes, the onset of late-replicating heterochromatin, and the lengthening of S phase in cycle 14. How Cdk1 triggers origin firing in pre-MBT cycles (e.g., cycle 13) and how late origins are specified and fired in cycle 14 (???) are unknown.