- 108 Dorothy Enslow Combs Cancer Research Building
Ph.D. University of Illinois Chicago
Postdoctoral Studies Stanford University
Research Description: My laboratory studies DNA repair mechanisms and we are interested in how alterations in DNA repair impact disease processes. Nucleotide excision repair (NER) is a major pathway for the removal of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts produced by UV light. It also removes a wide variety of bulky adducts formed by chemical agents including carcinogens and chemotherapeutic drugs. 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 lesions 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 lesions from the remainder of the genome. There are 3 areas related to nucleotide excision repair that we are currently investigating.
(1) Inherited defects in NER genes predispose humans to cancer; this is clearly illustrated by the disease xeroderma pigmentosum (XP). However it is less clear, how the efficiency of NER may vary among different individuals in a general (non-XP) population and how variations in the efficiency of NER among individuals may impact their risk for developing diseases such as cancer or impact the aging process. We are measuring NER efficiency in peripheral blood mononuclear cells (PBMCs) that we isolate from individual blood samples obtained from individuals who reside in Kentucky using a slot-blot method to quantify the removal of DNA damage. We are determining the influence of different demographic factors such as age, gender and ethnicity on individual NER efficiency. The ultimate goal is to evaluate whether individual NER efficiencies can be used as a predictor of individuals who are at risk for developing cancer or other disease states.
(2) 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.
Holcomb, N., Goswami, M, Han, S.G., Clark, S., Orren, D.K., Gairola, C. G., Mellon, I. (2016) Exposure of Human Lung Cells to Tobacco Smoke Condensate Inhibits the Nucleotide Excision Repair Pathway. PLoS One, 11(7):e0158858. doi: 10.1371/journal.pone.0158858.
Holcomb, N., Goswami, M, Han, S.G., Scott, T., D’Orazio, J., Orren, D.K., Gairola, C. G., Mellon, I. (2017) Inorganic arsenic inhibits the nucleotide excision repair pathway and reduces the expression of XPC protein, DNA Repair, Apr;52:70-80. doi: 10.1016/j.dnarep.2017.02.009. Epub 2017 Feb 16
(3) Certain chemotherapeutic agents introduce lesions that are removed by nucleotide excision repair. The efficacy of some types of chemotherapeutic agents in killing tumor cells may be related to differences in the efficiency of nucleotide excision repair among different individuals. We are currently developing strategies to determine if individual NER efficiency can be used as predictor of how patients will respond to treatment with certain chemotherapeutic agents.