DNA topoisomerases maintain the topology of DNA needed for cell growth and division and are targets for a host of anticancer drugs. They interact with certain forms of DNA damage that stabilize the covalently linked DNA breaks formed during their catalytic mechanism. Since both topoisomerase-mediated DNA breaks and sites of DNA damage promote mutagenesis and chromosomal aberrations that cause cancer, it is important to understand the significance of topoisomerase interactions with DNA lesions and the effect of these interactions on the processing of DNA damage. The focus of this proposal is the potential role of topoisomerases in nucleotide excision repair (NER) and the possible interplay between these systems in altering genomic stability. NER is responsible for the removal of bulky lesions from DNA. When located in a topoisomerase cleavage Site on DNA, these lesions may become internalized within the stabilized enzyme-DNA complex. Therefore, topoisomerases may hinder or facilitate the recognition of the DNA damage by NER proteins. In vitro studies will be performed to determine interactions between topoisomerase complexes and NER proteins involved in recognizing DNA lesions. To assess how topoisomerase activity affects the rate of NER, the repair capacity of yeast having wild-type or diminished levels of topoisomerase activity will be monitored. Studies with normal and XP human fibroblasts will be conducted to determine correlations between increases in topoisomerase-DNA complex levels and rates of TCR and GGR following UV irradiation or benzo[a]pyrene diol epoxide exposure. Results may indicate a specific interaction between the respective NER protein and topoisomerase. Findings from the proposed work will bring new insight into the molecular epidemiology of cancer.
| Cline, Susan D; Hanawalt, Philip C (2006) Topoisomerase deficiencies subtly enhance global genomic repair of ultraviolet-induced DNA damage in Saccharomyces cerevisiae. DNA Repair (Amst) 5:611-7 |
