Cdc48/p97 Segregase Is Modulated by Cdk to Bisect Cyclin Fate

Abstract

Cells sense and integrate a myriad of signals during G1 before commitment to DNA replication and division, and a rapid response to prevent cell cycle entry is of crucial importance for proper cell development and adaptation. Here we show that Cln3, the most upstream G1 cyclin acting at Start, undergoes a challenging ubiquitination step that is also required for its full activation. Segregase Cdc48/p97 prevents degradation of ubiquitinated Cln3, and concurrently stimulates its ER release and nuclear accumulation to trigger Start. Cdc48/p97 phosphorylation at conserved Cdk target sites is important for recruitment of specific cofactors and, in both yeast and mammalian cells, for efficient G1-cyclin activation. Cdk-dependent modulation of Cdc48 would subjugate G1 cyclins to fast and reversible state switching, thus arresting cells promptly in G1 at developmental or environmental checkpoints, but also resuming G1 progression immediately after proliferative signals reappear.