S phase

S phase (Synthesis phase) is the phase of the cell cycle in which DNA is replicated, occurring between G 1 phase and G 2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S-phase are tightly regulated and widely conserved.

S phase (Synthesis phase) is the phase of the cell cycle in which DNA is replicated, occurring between G 1 phase and G 2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S-phase are tightly regulated and widely conserved.

Regulation

Entry into S-phase is controlled by the G1 restriction point (R), which commits cells to the remainder of the cell-cycle if there is adequate nutrients and growth signaling. This transition is essentially irreversible; after passing the restriction point, the cell will progress through S-phase even if environmental conditions become unfavorable. Accordingly, entry into S-phase is controlled by molecular pathways that facilitate a rapid, unidirectional shift in cell state. In yeast, for instance, cell growth induces accumulation of Cln3 cyclin, which complexes with the cyclin dependent kinase CDK2. The Cln3-CDK2 complex promotes transcription of S-phase genes by inactivating the transcriptional repressor Whi5. Since upregulation of S-phase genes drive further suppression of Whi5, this pathway creates a positive feedback loop that fully commits cells to S-phase gene expression. A remarkably similar regulatory scheme exists in mammalian cells. Mitogenic signals received throughout G1-phase cause gradual accumulation of cyclin D, which complexes with CDK4/6. Active cyclin D-CDK4/6 complex induces release of E2F transcription factor, which in turn initiates expression of S-phase genes. Several E2F target genes promote further release of E2F, creating a positive feedback loop similar to the one found in yeast.

DNA replication

Throughout M phase and G1 phase, cells assemble inactive pre-replication complexes (pre-RC) on replication origins distributed throughout the genome. During S-phase, the cell converts pre-RCs into active replication forks to initiate DNA replication. This process depends on the kinase activity of Cdc7 and various S-phase CDKs, both of which are upregulated upon S-phase entry. Activation of the pre-RC is a closely regulated and highly sequential process. After Cdc7 and S-phase CDKs phosphorylate their respective substrates, a second set of replicative factors associate with the pre-RC. Stable association encourages MCM helicase to unwind a small stretch of parental DNA into two strands of ssDNA, which in turn recruits replication protein A (RPA), an ssDNA binding protein. RPA recruitment primes the replication fork for loading of replicative DNA polymerases and PCNA sliding clamps. Loading of these factors completes the active replication fork and initiates synthesis of new DNA. Complete replication fork assembly and activation only occurs on a small subset of replication origins. All eukaryotes possess many more replication origins than strictly needed during one cycle of DNA replication. Redundant origins may increase the flexibility of DNA replication, allowing cells to control the rate of DNA synthesis and respond to replication stress.

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