During genotoxic stress, cells activate a pathway, called the DNA damage checkpoint, to signal that damage has occurred. The inactivation of this checkpoint pathway is associated with many types of cancer, especially lymphoma and leukemia. The great majority of these checkpoint genes are conserved from humans to yeast. In fact, many of these genes have human homologs implicated in tumorigenesis. This application proposes to examine the ways in which the DNA damage checkpoint impinges upon normal cellular physiology, and the repercussions of DNA damage when the pathway is not functioning correctly. We will continue our previous studies in which we identified proteins that are modified by phosphorylation and ubiquitination when cells are damaged. We will also expand upon these studies by determining the significance of these events and the mechanisms by which they alter protein function.