The primary aim of our research is to investigate the signal transduction pathways (checkpoints) that regulate the cellular responses to DNA damage and replication interference. Loss of function mutations in mammalian checkpoint genes compromise the response to DNA damage at the cellular level and at the level of the organism lead to a predisposition to cancer. My laboratory makes use of the complementary mammalian and budding yeast systems to define the protein machinery involved in the DNA damage checkpoint and DNA repair processes. Our research is focused on understanding the mechanism of DNA damage-induced cell cycle arrest, gene activation and DNA repair by studying the protein kinases, such as Chk1, that are activated in the DNA damage checkpoint pathways and their targets. An important question in the study of checkpoints concerns the organization of the signal transduction pathways and the possible relationship between the checkpoint response and DNA repair. Our recent work has shown biochemical and genetic links between the checkpoint kinases and proteins involved in DNA replication and repair. In the next few years, we will continue to address checkpoint mechanisms on several fronts in order to obtain a clearer view of the dynamic molecular processes triggered in the cellular response to DNA damage.