CDC6 - Regulation

Regulation

Cdc6p is normally present at high levels during the G1 phase of the cell cycle. This is partly because the CDC6 gene is only transcribed during G1 phase. On the onset of the S phase, Cdc6p gets phosphorylated by the Cdc28-Clb5-Clb6 complex (Cdk1) and consequently becoming inactivated. This has been shown by introducing mutations in Cdc6p at the consensus sites for Cdk1 phosphorylation (near the N-terminus) which inhibit degradation. The phosphorylation can furthermore be catalyzed by Cdc28-Cln. The inactivated Cdc6p is then targeted for degradation by SCFCDC4-dependent ubiquitinylation and afterwards degraded by the proteosome. Thus, the regulation of Cdc6p is tightly correlated to the activity of Cdk1 and since Cdk1-activity is oscillating once per cell cycle, the accumulation and degradation of Cdc6p also oscillates.

Two states can be distinguished. In the first state (during G1 phase) Cdk1-activity is low, Cdc6p can accumulate, hence the pre-RC can be formed but not activated. In the second state Cdk1-activity is high, Cdc6p becomes inactivated, hence the pre-RC is activated but not formed. This change assures that DNA replication is performed only once per cell cycle. It has been shown that overexpression of Cdc6p does not induce re-replication in cognate cells, probably due to inhibition through CDK that resets the cell cycle clock to G1. Nevertheless it has been suggested that regulation of Cdc6p is one of several redundant mechanisms that prevent re-replication of the DNA in eukaryotic cells.