Abstract
In preparation for dramatic morphogenetic events of gastrulation, rapid embryonic cell cycles slow at the mid-blastula transition (MBT). In Drosophila melanogaster embryos, down-regulation of cyclin-dependent kinase 1 (Cdk1) activity initiates this slowing by delaying replication of heterochromatic satellite sequences and extending S phase. We found that Cdk1 activity inhibited the chromatin association of Rap1 interacting factor 1 (Rif1), a candidate repressor of replication. Furthermore, Rif1 bound selectively to satellite sequences following Cdk1 down-regulation at the MBT. In the next S phase, Rif1 dissociated from different satellites in an orderly schedule that anticipated their replication. Rif1 lacking potential phosphorylation sites failed to dissociate and dominantly prevented completion of replication. Loss of Rif1 in mutant embryos shortened the post-MBT S phase and rescued embryonic cell cycles disrupted by depletion of the S phase–promoting kinase, cell division cycle 7 (Cdc7). Our work shows that Rif1 and S phase kinases compose a replication timer controlling first the developmental onset of late replication and then the precise schedule of replication within S phase. In addition, we describe how onset of late replication fits into the progressive maturation of heterochromatin during development.
Highlights
Eukaryotic DNA replication begins at many locations throughout the genome, known as origins
During the rapid cell cycles before the mid-blastula transition (MBT), we show that the cyclin-dependent kinase 1 (Cdk1) prevents Rap1 interacting factor 1 (Rif1) from slowing down DNA replication
We have discovered that Rap1 interacting factor 1 (Rif1)—a conserved protein that interacts with protein phosphatase 1 (PP1) and impacts telomere biology, DNA damage responses, and replication timing [32][33][34][35]—is an important regulator of early developmental changes in cell cycle timing
Summary
Eukaryotic DNA replication begins at many locations throughout the genome, known as origins. Different origins initiate at different times during S phase on a schedule governed by an elusive replication timing program. The time it takes to duplicate the genome, the length of S phase, is set by the time when the last sequence completes replication. Late replication is presented as a general property of heterochromatin, but how this property arises is unknown [2]. Late replication is properly viewed as a feature that must be imparted to the heterochromatin at the beginning of every new generation.
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