The goals of this proposal are to determine the time of surveillance of DNA cross-links in the cell cycle and the timing and mechanism of repair of the cross-links in the cell cycle Bi-functional reagents such as cisplatin can cross-link DNA. Such damage interfere with cellular processes of transcription and replication and the agents are useful in treatment of cancer. Mechanisms for the repair of the DNA damage caused by cross-linking are not understood in eukaryotic cells. Cells from patients with the disease Fanconi anemia show a markedly increased sensitivity to agents which cross-link DNA, among all the forms of DNA damage tested. This illustrates the cross-links require specific steps for repair. Although yeast does not apparently contain orthologs to the Fanconi anemia genes isolated, because of the powerful genetic system and the detailed analysis of the cell cycle, yeast offers a good system for investigating eukaryotic response to DNA cross-links. This proposal will test whether or not DNA cross-links are surveyed and assessed at a particular point in the cell cycle, rather than throughout the cell cycle and whether or not the repair of DNA cross-links is segregated to a particular time in the cell cycle. This information is needed for understanding the mechanisms for DNA cross-link repair and the gene products which are involved. Ultimately we want to define the components regulating the cell cycle checkpoints for DNA cross-links. To develop these studies, we will isolate and characterize additional cross-linker sensitive mutants.
| Li, Xiaorong; Moses, Robb E (2003) The beta-lactamase motif in Snm1 is required for repair of DNA double-strand breaks caused by interstrand crosslinks in S. cerevisiae. DNA Repair (Amst) 2:121-9 |
| Moses, R E (2001) DNA damage processing defects and disease. Annu Rev Genomics Hum Genet 2:41-68 |
| Grossmann, K F; Ward, A M; Matkovic, M E et al. (2001) S. cerevisiae has three pathways for DNA interstrand crosslink repair. Mutat Res 487:73-83 |
| Grossmann, K F; Ward, A M; Moses, R E (2000) Saccharomyces cerevisiae lacking Snm1, Rev3 or Rad51 have a normal S-phase but arrest permanently in G2 after cisplatin treatment. Mutat Res 461:13-Jan |
| Grossmann, K F; Brown, J C; Moses, R E (1999) Cisplatin DNA cross-links do not inhibit S-phase and cause only a G2/M arrest in Saccharomyces cerevisiae. Mutat Res 434:29-39 |
