Loss of genetic integrity is a critical factor in the process of malignant transformation and developing resistance of tumors to anti-cancer agents. Genetic instability often is a result of non-functional checkpoint controls. Therefore, understanding the mechanisms of checkpoint controls is of great importance. The S-phase checkpoint coordinates progression of the cell cycle with DNA replication. One critical issue concerns the mechanism regulating the S-phase checkpoint. In S. cerevisiae, progression into mitosis is regulated in part by transcriptional activation of a component of the anaphase promoting complex, Cdc20p. Recent evidence strongly suggests that S-phase checkpoint proteins, Rad23p and Ddi1p delay mitosis in response to a DNA replication block through silencing of CDC20. This proposal focuses on a detailed analysis of the role that Rad23p and Ddi1p play in regulation of CDC20 expression, as well the mechanism of their activation.
