Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY Gross chromosomal rearrangements (GCRs) are mutations that underlie many genetic diseases. Many cancers have increased accumulation of GCRs, which likely represents a type of mutator phenotype thought to be important for the development and progression of these cancers. Consistent with this, some inherited cancer susceptibility syndromes result from genetic defects that cause increased accumulation of GCRs in model systems. While many pathways thought to play a role in preventing GCRs have been studied, a comprehensive understanding of the genes, pathways and mechanisms that prevent accumulation of GCRs is not available. Understanding these mechanisms will impact on human health for several reasons: 1) Identifying genes and mechanisms that suppress and promote GCRs will provide tools to identify causes of genome instability in cancer; 2) The development of PARP inhibitors for treating cancers with BRCA1 and BRCA2 defects has demonstrated that defects causing genome instability are potential therapeutic targets for cancer; and, 3) Understanding pathways that suppress accumulation of GCRs, including identifying synthetic lethal partner genes for these pathways, will provide critical information for guiding developing of novel cancer diagnostics and therapeutic approaches for use in personalized approaches to cancer treatment. The goal of this proposal is to use Saccharomyces cerevisiae to identify genes, pathways and mechanisms that suppress GCRs that will then guide the development of assays for the formation of GCRs in human cells. Key related objectives are to identify chromosomal features and aberrant DNA repair mechanisms that contribute to the formation of GCRs and to identify human genes in which defects cause genome instability in cancer. The proposed studies will build on the results of work supported by this project that have resulted in a series of quantitative assays for use in studying GCRs and have identified numerous genome instability suppressing (GIS) genes and cooperating GIS genes that suppress the accumulation of GCRs in S. cerevisiae. The following lines of research will be carried out: 1) The mechanistic features of selected pathways that suppress GCRs will be investigated, focusing on Tor2 (a tumor suppressor homologue), the cohesion and condensin complexes, and Exonuclease 1; 2) Genetic studies and whole genome sequencing will be used to identify the genes and mechanisms that suppress or promote GCRs mediated by the formation of large loop ssDNA hairpin-mediated GCRs and study the genomic features that underlie the formation of specific GCRs; 3) The mechanistic and genetic features of the formation of individual GCRs will be studied using a newly developed assay that allows monitoring of the formation of an individual GCR by PCR; and, 4) GCR assays for use in human cells will be developed and used to investigate defects in human GIS genes. These studies will provide a comprehensive picture of the pathways and mechanisms that prevent GCRs in S. cerevisiae and provide insights into the origin of genome instability in cancer.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).