Sic1

Sic1 is a regulatory protein in the budding yeast Saccharomyces cerevisiae that functions as a cyclin-dependent kinase (CDK) inhibitor. It is encoded by the SIC1 gene (also known as YBR280C) and plays a key role in controlling the G1 to S phase transition by restraining Cdc28 kinase activity, particularly in association with S-phase cyclins.

In terms of mechanism, Sic1 binds to Cdc28 in complex with S-phase cyclins such as Clb5 and Clb6, inhibiting kinase activity and preventing premature initiation of DNA replication. The inhibition is reinforced by the action of G1 cyclin–CDK complexes (Cln1–3 with Cdc28) that phosphorylate Sic1, creating phosphorylation-dependent degron motifs. These motifs are recognized by the SCF(Cdc4) ubiquitin ligase, leading to ubiquitination and proteasomal degradation of Sic1. The removal of Sic1-mediated inhibition allows Clb-Cdc28 activity to promote S-phase entry.

Regulation of Sic1 is crucial for proper cell-cycle timing and cell-size control in yeast. Alterations in SIC1 expression or its degradation can shift the G1/S boundary, cause inappropriate timing of replication, or affect cellular fitness. Sic1 is part of a broader network that ensures a robust and irreversible transition from G1 into S phase.

Evolutionarily, Sic1 is a functional analog of mammalian Cip/Kip CDK inhibitors (such as p21 and p27) but is not a direct homolog. It highlights evolutionary strategies for controlling CDK activity to regulate cell cycle progression.