ACKNOWLEDGEMENTSWe would like to thank Vitaly Citovsky for strains and plasmids. We also thank Simonetta Piatti for critical reading of the manuscript and Chiara Francavilla for initial work on this project. This work has been partially supported by grants from AIRC (to L. Report Subcellular Localization of the Cyclin Dependent Kinase Inhibitor Sic1 is Modulated by the Carbon Source in Budding Yeast ABSTRACTThe cyclin dependent kinase inhibitor Sic1 and the cyclin Clb5 are essential regulators of the cyclin dependent kinase Cdc28 during the G 1 to S transition in budding yeast. Yeast enters S phase after ubiquitin-mediated degradation of Sic1, an event triggered by Cln1, 2-Cdc28 mediated phosphorylation. We recently showed that Sic1 is involved in carbon source modulation of the critical cell size required to enter S phase. Here we show that the amount and sub-cellular localization of Sic1 are also carbon source-modulated. We identify a bipartite nuclear localization sequence responsible for nuclear localization of Sic1 and for correct cell cycle progression in a carbon-source dependent manner. Similarly to Cip/Kip proteins-Sic1 mammalian counterparts-Sic1 facilitates nuclear accumulation of its cognate cyclin, since cytoplasmic building-up of Clb5 is observed upon switching off expression of the SIC1 gene. Our data indicate a previously unrecognized inhibitor/activator dual role for Sic1 and put it among key molecules whose activity is regulated by their nuclear-cytoplasmic localization.