DNA damage-induced cell cycle checkpoints have been postulated to be important in maintaining genetic stability by arresting or delaying the cell cycle to allow time for repair of recombinogenic DNA damage. Loss-of-function mutations that abolish checkpoints and increase genetic instability have been observed in cancer cells and may contribute to rapid proliferation and/or resistance to chemotherapeutic drugs and radiation therapy. Cell cycle checkpoint genes may function in a signal transduction pathway in which the presence of DNA damage is relayed to both the cell cycle machinery and the transcription apparatus to upregulate DNA repair genes. The purpose of this proposal is to elucidate the genetic pathway by which the Saccharomyces cerevisiae RAD9 checkpoint reduces genetic instability that results from homologous recombination between repeated sequences (ectopic recombination). We have previously described a chromosomal translocation assay that can measure genetic instability in yeast rad9 mutants.
The first aim i s to identify specific genes or combinations of genes in the RAD9- mediated signal transduction pathway which reduce the radiation- associated stimulation of translocations.
The second aim i s to examine the contribution of other cell cycle checkpoints in maintaining genetic stability.
The third aim i s to understand whether checkpoints also reduce the radiation-associated recombination between yeast Ty elements. The results obtained in this study may also elucidate current ideas concerning genomic stability in eukaryotic organisms: 1) that elevated levels of recombinases may be important in DNA repair of double-strand breaks (DSBs) generated by DNA replication, 2) that signal transduction pathways that trigger the G2-M checkpoint and control genetic stability are redundant, 3) that the non-random accumulation of genetic changes observed in checkpoint mutants may partially result from recombination between retrotransposons.
| Fasullo, Michael T; Sun, Mingzeng (2017) Both RAD5-dependent and independent pathways are involved in DNA damage-associated sister chromatid exchange in budding yeast. AIMS Genet 4:84-102 |
| Fasullo, Michael; Tsaponina, Olga; Sun, Mingzeng et al. (2010) Elevated dNTP levels suppress hyper-recombination in Saccharomyces cerevisiae S-phase checkpoint mutants. Nucleic Acids Res 38:1195-203 |
| Fasullo, Michael; Sun, Mingzeng (2008) UV but not X rays stimulate homologous recombination between sister chromatids and homologs in a Saccharomyces cerevisiae mec1 (ATR) hypomorphic mutant. Mutat Res 648:73-81 |
