Genomic Instability, Epigenetics and Metabolism
Colleges & Departments:
College of Medicine, Department of Toxicology and Cancer Biology
My laboratory studies DNA repair mechanisms and we are interested in how alterations in DNA repair impact disease processes, in particular the etiology of certain forms of cancer. Nucleotide excision repair (NER) is a major DNA repair pathway that removes a wide variety of different bulky types of DNA damage formed by exposures to UV light and chemical carcinogens. It is a complex multi-step process that is comprised of two subpathways in E. coli, yeast and mammals. One subpathway is termed transcription-coupled repair (TCR) which selectively removes DNA damage from the transcribed strands of expressed genes. This subpathway of DNA repair I co-discovered with Philip Hanawalt and colleagues. The other subpathway is termed global genome repair (GGR) which removes DNA damage from the remainder of the genome.
There are 3 areas related to nucleotide excision repair that we are currently investigating.
- Cigarette smoke contains numerous carcinogenic compounds that introduce modifications to DNA that are removed by the NER pathway. When these DNA modifications persist they can lead to the formation of mutations that very likely play a major role in lung cancer development. Consequently, agents that inhibit the NER pathway would likely enhance the carcinogenic potential of agents present in cigarette smoke and contribute to the development of lung cancer. We have recently found that exposure of human lung cells in culture to cigarette smoke or trace metals, compounds found in cigarette smoke, inhibits NER. Hence, exposure to tobacco smoke not only introduces DNA damage but it also inhibits the removal of DNA damage and both processes may be important in the etiology of lung cancer. We are currently investigating the specific mechanisms that mediate the inhibition of NER by tobacco smoke and heavy metals using cell culture models.
- We are investigating whether individual NER efficiency is altered in patients with lung cancer and whether individual NER efficiencies are influenced by exposures to trace metals in the environment and/or smoke exposure. Appalachian Kentucky has inordinately high rates of lung cancer. While tobacco smoke is the primary risk factor for almost all lung cancer, smoking habits in this region of Kentucky do not explain the elevated rates of lung cancer in Appalachia compared with other regions of the state. We are measuring NER efficiency in peripheral blood mononuclear cells (PBMCs) that we isolate from individual blood samples obtained from lung cancer patients and control individuals who reside in the 5th district of Appalachian Kentucky. We will compare the NER efficiencies that we measure in each individual with lung cancer status, trace metal exposure and nicotine exposure. The ultimate goal is to evaluate whether individual NER efficiencies can be used as a predictor of individuals who are at risk for developing lung cancer.
- Inherited defects in NER genes predispose humans to cancer. We are currently investigating whether polymorphisms and/or acquired somatic mutations in NER genes can also be involved in the etiology of certain types of cancer. We are characterizing cell lines derived from different tumor types for alterations in NER. In addition, we are carrying out structure/function studies to investigate the functional significance of variations in NER genes.
- Metastasis suppressor NM23-H1 promotes repair of UV-induced DNA damage and suppresses UV-induced melanomagenesis. Jarrett SG, Novak M, Dabernat S, Daniel JY, Mellon I, Zhang Q, Harris N, Ciesielski MJ, Fenstermaker RA, Kovacic D, Slominski A, Kaetzel DM. Cancer Res 72:133-143, 2012.
- Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene. Mellon I, Spivak G and Hanawalt PC. Cell 51:241-249, 1987.
- Induction of the Escherichia coli lactose operon selectively increases repair of its transcribed strand. Mellon I and Hanawalt PC. Nature 342:95-98, 1989.
- Polymorphisms in the human xeroderma pigmentosum group: A gene and their impact on cell survival and nucleotide excision repair. Mellon I, Hock T, Reid R, Porter PC and States JC. DNA Repair 1:531-546, 2002.
- XP-A cells complemented with Arg228Gln and Val234Leu polymorphic XPA alleles repair BPDE-induced DNA damage better than cells complemented with the wild type allele. Porter PC, Mellon I and States JC. DNA Repair 4:341-349, 2005.