Celt cycle checkpoint pathways in yeast and humans

Cell cycle checkpoints are biochemical pathways that control the timing and order of cell cycle events. The ability to coordinate cell cycle transitions in response to genotoxic stress is critical to the maintenance of genomic stability. Mutations in mammalian genes that abrogate this response, such as p53 and ATM, cause a genetic predisposition to cancer. In yeast, several genes have been identified that control the response to DNA damage, replication blocks or both, including the MEC, SAD, RAD, and DUN genes. DNA polymerase epsilon (POL2/DUN2) is a potential sensor of DNA replication blocks that links the replication machinery to the S phase checkpoint. RAD53 encodes a protein kinase that controls cell cycle arrest and transcriptional responses to DNA damage and DNA replication blocks, including activation of the DUNi kinase which is responsible for the transcriptional response to DNA damage. MEC1 encodes a protein related to the human ATM kinase. Like RAD53, it is involved in the transcriptional and cell cycle responses. We have been exploring the organization of this pathway in S. cerevisiae. We will discuss the evidence for a particular order for function of these genes and describe new genes we have recently identified in this pathway. Our results suggest that the primary function of these pathways is to repair DNA damage as opposed to controlling the cell cycle. Other checkpoints such as those that control developmental decisions may also be discussed.