Both Sic1 and Cdc6 play a role as stoichiometric inhibitors of Cdk kinases. Sic1 is an inhibitor of Clb2-dependent and Clb5-dependent kinases. Cdc6 is an inhibitor of Clb2-dependent kinase only. In addition to its role as a CKI, Cdc6 is a licensing factor for DNA replication. In our model, we only consider the role of Cdc6 as a CKI.
- Inhibits Clb2-dependent and Clb5-dependent Cdc28 kinases, but not Cln kinases (Schwob, et al., 1994).
- Mutants with Sic1 deletion are viable, they initiate DNA synthesis at a much smaller size than the wild type (Schneider et al., 1996).
- Deletion of Sic1 causes genome unstability (Nugroho & Mendenhall, 1994; Lengronne & Schwob, 2002).
- Licensing factor involved in the initiation of DNA replication (Botchan, 1996). It interacts with ORC (Origin Recognition Complex) for loading of the MCM proteins on chromatin (Donovan et al., 1997; Piatti et al., 1995).
- Inhibits Clb2/Cdc28 (Calzada et al., 2001; Elsasser et al., 1996; Bueno & Russell, 1992), but not Clb5/Cdc28 (Archambault et al., 2003).
- The mutant cdc6∆2-49 (the CKI role of Cdc6 is removed by deletion of the n-terminal 47 base pairs, but its role as a DNA licensing factor remains intact) is viable (Calzada et al., 2001; Nguyen et al., 2001).
Level and regulation:
- Protein level is high at the end of mitosis and during G1 phase then becomes unstable after Start (Donovan et al., 1994;Schwob, et al., 1994; Verma et al., 1997b).
- Transcription is activated by Swi5 (Knapp et al., 1996). Swi5 activity is regulated by nuclear localization. Clb2-dependent phosphorylation of Swi5 prevents it from entering the nucleus, resulting in inactivation (Nasmyth et al., 1990), whereas Cdc14 reverse this effect (Visintin et al., 1998).
- Phosphorylation by Cdk/cyclin complexes targets Sic1 for degradation by the SCF pathway (Verma et al., 1997b).
- Dephosphorylation and stabilization by Cdc14 at the end of mitosis (Visintin et al., 1998).
- mRNA and protein fluctuate throughout the cell cycle and their levels are high in late M phase until the end of the G1 phase (Zhou & Jong, 1990; Liang & Stillman, 1997; Donovan et al., 1997).
- Transcription is activated by Swi5 and MBF (Piatti et al., 1995).
- Degradation by SCF when in the phosphorylated form (Drury et al., 1997; Elsasser et al., 1999).
- Located in the cytoplasm during S phase until the end of anaphase, then relocalized to the nucleus (Piatti et al., 1996).