Cell Cycle and Checkpoint Control

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DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand how the cell division cycle is regulated during a normal cell cycle (cell cycle control) and how cell cycle progression is prevented when unreplicated or damaged DNA is detected (checkpoint control). The passage of cells from one stage of the cell cycle to the next is regulated by several distinct controls that act on the transcription of cyclin genes; the degradation of cyclin proteins; the modification of the cyclin-dependent protein kinases (Cdks) by both reversible phosphorylation and by association with regulatory subunits; and finally by intracellular compartmentalization of cyclin/Cdk components and their regulators. The Cdc25 protein phosphatases positively regulate the cell division cycle by activating CDKs and they are also targets of checkpoint control. In humans and rodents, there are three members of the Cdc25 family, designated Cdc25A, B and C. Studies aimed at elucidating how the Cdc25A protein phosphatase is regulated throughout the cell division cycle and in response to checkpoint activation are proposed. In addition, studies aimed at distinguishing the individual contributions made by Cdc25A, Cdc25B and Cdc25C to cell cycle progression and checkpoint control in both mouse and human cells are proposed. Finally, studies will be performed to elucidate how the checkpoint kinases, Chkl and Chk2 are activated by unreplicated DNA and/or genotoxic stress and how these kinases interface with the cell cycle machinery to cause cell cycle delays in the presence of unreplicated or damaged DNA. Because many cancers are neither curable using existing strategies nor readily detectable at early stages there is a need to identify new targets that can be used both as diagnostic probes and as therapeutic targets. The studies outlined in this proposal investigate basic mechanisms of cell cycle control and checkpoint control. Proteins involved in these pathways may one day be used as diagnostic markers or as targets for designing anti-proliferative drugs.