Networks that Suppress Genome Instability
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, the speaker and his research group 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 a breakpoint 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. Using these assays and a novel genetic screen design, they have identified 188 genes in which defects cause increased GCRs and an additional 325 genes in which mutations only cause increased GCRs when combined with a second mutation thus defining multiple pathways that prevent GCRs. Unexpectedly, they found that there are specific pathways that suppress duplication-mediated GCRs and identified sequences that are hotspots for the formation of GCRs. They are now using the human homologues of the yeast genome instability suppressing genes to examine the genetics of genome instability in human cancers by mining cancer genomics data sets.
About the speaker
Prof. Richard Kolodner received his PhD in Biological Sciences from the University of California at Irvine in 1975. Following his post-doctoral work at Harvard, he was Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School and Professor of Cancer Biology at the Dana-Farber Cancer Institute. He joined the University of California at San Diego in 1997, and is currently Distinguished Professor and Head of Laboratory of Cancer Genetics of the Ludwig Institute for Cancer Research.
Prof. Kolodner’s research interests focus on the genetic and biochemical mechanisms of genetic recombination, DNA repair and suppression of spontaneous mutations primarily using Saccharomyces cerevisiae as a model system. Work in S. cerevisiae falls in two interrelated areas, which include the analysis of the proteins and genes that function in DNA mismatch repair, and elucidation of the pathways that prevent translocations and other types of gross chromosomal rearrangements, and the analysis of the proteins that function in these pathways. His lab also has research interests in the area of investigating the genetics of cancer susceptibility and development that follows on previous studies showing that a common cancer susceptibility syndrome, Lynch Syndrome (hereditary non-polyposis colorectal cancer), is due to inherited defects in DNA mismatch repair genes. This work is focused on understanding whether genes that prevent genome instability act as tumor suppressor genes in mice and humans and on the development of therapeutic approaches to target cells with defects that cause increased genome instability.
Prof. Kolodner received the Merit Award from the US National Institutes of Health in 1992. He is a Member of the US National Academy of Sciences, the Institute of Medicine, the American Association for Cancer Research, the American Society for Microbiology and the American Society for Biochemistry and Molecular Biology.
