Abstract KP01: Identification of genes and pathways that prevent genome instability

Abstract

Abstract The genome of many cancers is characterized by ongoing genome instability; however, the causes of genome instability in cancer are not well understood. To understand the control genome instability, we developed three types of genetic assays for measuring the rate of accumulating gross chromosomal rearrangements (GCRs) in the yeast Saccharomyces cerevisiae - one that detects GCRs containing breakpoints in single copy sequences, a second that detects GCRs mediated by segmental duplications, and a third that detects GCRs mediated by Ty elements which are similar to mammalian LINE elements. Initial studies characterizing these three types of assays found that there are specific pathways that suppress duplication-mediated GCRs and identified sequences that are hotspots for the formation of GCRs. We have subsequently used these three assays to perform a genetic screen of the non-essential genes in S. cerevisiae to identify the genetic network that acts to prevent genome instability. This screen involved three steps: a novel bioinformatics screen to identify and prioritize candidate genome instability suppressing genes; a biological genetic screen to identify which of the predicted genes actually suppress genome instability; and a biological genetic screen to identify interacting genes. As a result of these screens, we have identified 184 genes in which defects cause increased GCRs and an additional 459 genes in which mutations only cause increased GCRs when combined with a second mutation thus defining multiple pathways that prevent GCRs. Control experiments indicated that this approach led to the identification of greater than 95% of the non-essential genes that act to suppress genome instability. In a second screen, we identified 44 essential genes in which defects caused increased GCRs. We are now beginning to use the S. cerevisiae genome instability suppressing genes to predict the mammalian genome instability genetic suppressing network. Citation Format: Richard Kolodner, PhD. Identification of genes and pathways that prevent genome instability [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr KP01.