(From the applicant?s abstract) Tumorigenesis is characterized by the accumulation of genetic alterations that result in an increase in cell proliferation and a decrease in programmed cell death (apoptosis). In metazoans, when damage to the genome is excessive, cells undergo apoptosis. Recently, a conserved genetic pathway of DNA damage cell cycle arrest and apoptosis has been identified using C. elegans. In order to understand the mechanisms of DNA damage-induced cell cycle arrest and apoptosis, we plan to use C. elegans for genetic and molecular analysis of these pathways.
The specific aims of the project are: 1) Clone dam-1 and characterize its role in DNA damage-induced germ cell death, 2) generate and characterize null alleles in three DNA damage checkpoint genes, and 3) isolate and genetically characterize new dam (DNA damage response) mutants. Cloning dam-1 will be done using a combinatorial positional cloning and candidate gene approach. Using reverse genetics, checkpoint deletion mutants will be isolated and characterized for their involvement in DNA damage induced apoptosis and cell cycle arrest. Forward genetics will be employed to identify new, possibly metazoan specific, dam mutants that are defective in their apoptotic response to DNA damage. This work will lead to a greater understanding of the genetic and molecular pathway(s) that regulate DNA damage-induced cell cycle arrest and apoptosis.
| Degtyareva, Natasha P; Greenwell, Patricia; Hofmann, E Randal et al. (2002) Caenorhabditis elegans DNA mismatch repair gene msh-2 is required for microsatellite stability and maintenance of genome integrity. Proc Natl Acad Sci U S A 99:2158-63 |
| Hofmann, E Randal; Milstein, Stuart; Boulton, Simon J et al. (2002) Caenorhabditis elegans HUS-1 is a DNA damage checkpoint protein required for genome stability and EGL-1-mediated apoptosis. Curr Biol 12:1908-18 |
