By Levi Clancy for Student Reader on
Eukaryotic chromosomes are replicated from multiple origins. Initiation of replication from these origins occurs throughout S phase. Some origins fire in early S, some in late S phase. However, no eukaryotic origin initiates more than once per S phase.
S phase continues until replication from multiple origins along the length of each chromosome results in complete replication of the entire chromosome. These two factors (SCF and APC/C) ensure that the correct gene copy number is maintained as cells proliferate.
How do the S-phase cyclin-CDKs activate DNA replication? And how is the process of DNA replication regulated so that each origin fires one time, and only one time during S-phase? In eukaryotes, DNA replication at an origin initiates only one time during S-phase. What mechanism accounts for this? In proliferating cells, how is this block to re-initiation at a replication origin overcome in preparation for replication during the next S-phase?
The Origin Recognition Complex binds the origin of replication and then recruits replication proteins. Once S-cyclin+CDK activates the complexes, replication can commence. The DNA replication proteins are deactivated and/or fall off the genome, or actively move along the DNA (for example, the DNA Polymerase). These DNA replication complexes are not expressed so the DNA replication complex cannot reform.
The problem of reassembling the pre-replication complex is resolved later via mitotic cyclins, which activate expression of DNA replication proteins but leave the DNA replication complexes inactive. Mitotic cyclins are quickly degraded during telophase and thus do DNA replication complexes are not expressed during S-phase.
What mechanism accounts for the sudden onset of DNA synthesis in S. cerevisiae? Active S-cyclin+CDK phosphorylates and activates proteins that initiate DNA synthesis at origins of replication. However, S-cylin+CDK is inhibited by Sic1 while S-phase cyclin and S-phase CDK is being produced.
The inhibitor is then precipitously degraded by Late-G1-Cyclin+CDK. This de-repression unleashes a massive wave of active S-cyclin+CDK, as opposed to a slow rise in activity that would have occurred without the repressor. This permits the sudden activation of large numbers of DNA replication complexes and thus the sudden onset of DNA synthesis.