Genome instability is one of the hallmarks of cancer. However, the mechanisms that protect the genome against spontaneous gross chromosomal rearrangements (GCRs) are not well understood. In recent years several pathways have been identifi ed that protect the genome against spontaneous GCRs. One such pathway involves cyclin dependent kinases (CDKs). CDKs are proline-directed serine/threonine kinases that function in complex with cyclins. CDKs drive the cell cycle, are improperly regulated i n tumors, and unscheduled CDK activition results in increased GCR rates. However, the nature of the targets of CDKs that affect genome stability remains obscure, and few bona fide CDK targets have been identified. This project proposal is aimed at identif ication of the pathways that are controlled by CDKs and which function in genome maintenance and in cell survival during DNA damage. Using the model organism Saccharomyces cerevisiae, I plan to unravel the genetic pathways involving CDC28 (the yeast CDK t hat controls the cell cycle) using an automated chemical-genetics screen. Furthermore, I will verify putative in vivo targets of Cdc28 and map the sites that get phosphorylated by Cdc28. Finally, I will determine the function of these targets in maintenan ce of genome stability and in cell survival during DNA damage.