Genomic Instability, Epigenetics and Metabolism
Colleges & Departments:
College of Medicine, Department of Toxicology and Cancer Biology
Our laboratory focuses on the interrelationships between DNA damage and its repair to human health outcomes, primarily the development of cancer and other age-related diseases. One area of emphasis is the function of the human RecQ helicase enzymes required for maintaining genome stability. Although there are five human RecQ helicases, we primarily investigate the roles of WRN and BLM that are deficient in the premature aging and cancer-prone hereditary diseases Werner and Bloom syndromes, respectively. Findings from ours and others’ research indicate that WRN and BLM have roles in telomere maintenance and DNA recombination pathways; defects in these pathways result in 1) chromosomal instability that increases cancer susceptibility or 2) cellular senescence and apoptotic cell death that accelerates some tissue-specific aging phenotypes. While WRN has a definite impact on telomere stability, both WRN and BLM are currently also believed to participate in the ability of cells to properly resolve replication stress caused by DNA damage and other circumstances. Our research is focused on clarifying the specific functions of WRN and BLM in their respective pathways. We are also interested in targeting these pathways to potentially enhance the efficacy of certain cancer chemotherapeutic agents that damage DNA. Another area of recent study is investigation into the roles that exposures to specific environmental agents play in increasing cancer susceptibility. Our lab is particularly interested in the effects of metal and tobacco-related exposures on generation and repair of DNA damage with respect to lung and other cancers. This includes examination of 1) generation of DNA damage and/or alteration of DNA repair efficiency by specific compounds or complex mixtures, 2) differential repair efficiency of structurally distinct DNA lesions, and 3) relationships between environmental exposures, steady-state DNA damage burdens and cancer development. To this end, our lab has developed assays suitable for measuring and quantifying a broad spectrum of lesions (or subsets thereof) in DNA derived from experimental, clinical, and epidemiological samples. In collaborations with other researchers here at the University of Kentucky and elsewhere, we are implementing these assays in several scenarios related to cancer susceptibility. A significant portion of this research is centered on possible additional contributing factors that underlie the extremely high incidence of smoking-related lung cancer in Appalachian Kentucky.
- Replication fork regression in vitro by the Werner syndrome protein (WRN): Holliday junction formation, the effect of leading arm structure and a potential role for WRN exonuclease activity. Machwe A, Xiao L, Lloyd RG, Bolt E, and Orren DK. Nucleic Acids Res 35: 5729-5747, 2007.
- Werner syndrome: molecular insights into the relationships between defective DNA metabolism, genomic instability, cancer and aging. Orren DK. Front Biosci 11:2657-2671, 2006.
- The Werner and Bloom syndrome proteins catalyze regression of a model replication fork. Machwe A, Xiao L, Groden J, and Orren DK. Biochemistry 45:13939-13946, 2006.
- RecQ family members combine strand pairing and unwinding activities to catalyze strand exchange. Machwe A, Xiao L, Groden J, Matson SW, and Orren DK. J Biol Chem 280:23397-23407, 2005.
- TRF2 recruits the Werner syndrome exonuclease for processing of telomeric DNA. Machwe A, Xiao L, and Orren DK. Oncogene 23:149-156, 2004.