Commitment to the Cell Cycle and DNA Replication
In yeast, START defines a stage in G1 after which cells are irreversibly committed to the cell cycle. Molecularly, it is defined as the point when 50 percent of Whi5 has exited the nucleus.
The molecular events promoting entry into the cell cycle are conserved across species. G1 CDKs inhibit a transcriptional repressor. This allows the transcription of G1/S phase cyclin genes and other genes important for S phase.
Extracellular signals such as nutritional state (in yeast) and the presence of mitogens and anti-
Various polypeptide growth factors called mitogens stimulate cultured mammalian cells to proliferate by inducing expression of early response genes. Many of these genes encode transcription factors that stimulate expression of genes encoding the G1/S phase cyclins and E2F transcription factors.
The G1/S phase CDKs phosphorylate and inhibit Cdh1, the specificity factor that directs the anaphase-
In yeast, S phase CDKs are initially inhibited by Sic1. Phosphorylation marks Sic1 for ubiquitinylation by the SCF ubiquitin-
DNA replication is initiated from helicase loading sites known as replication origins.
Loading and activation of MCM helicases occur in mutually exclusive cell cycle states: MCM helicase loading can occur only when CDK activity is low (during early G1); MCM helicases are activated when CDK activity is high.
S phase CDKs and DDK trigger the initiation of DNA replication by recruiting MCM helicase activators to origins (see Figure 19-16).
Initiation of DNA replication occurs at each origin only once during the cell cycle because S phase CDKs activate the helicases and at the same time prevent additional helicases from loading onto DNA.
Cohesins establish linkages between the replicated DNA molecules, which are essential for their accurate segregation later in the cell cycle. This linking mechanism is coupled to DNA replication.