Abstract
Exposure to tobacco smoke is the number one risk factor for lung cancer. Although the DNA damaging properties of tobacco smoke have been well documented, relatively few studies have examined its effect on DNA repair pathways. This is especially true for the nucleotide excision repair (NER) pathway which recognizes and removes many structurally diverse DNA lesions, including those introduced by chemical carcinogens present in tobacco smoke. The aim of the present study was to investigate the effect of tobacco smoke on NER in human lung cells. We studied the effect of cigarette smoke condensate (CSC), a surrogate for tobacco smoke, on the NER pathway in two different human lung cell lines; IMR-90 lung fibroblasts and BEAS-2B bronchial epithelial cells. To measure NER, we employed a slot-blot assay to quantify the introduction and removal of UV light-induced 6–4 photoproducts and cyclobutane pyrimidine dimers. We find a dose-dependent inhibition of 6–4 photoproduct repair in both cell lines treated with CSC. Additionally, the impact of CSC on the abundance of various NER proteins and their respective RNAs was investigated. The abundance of XPC protein, which is required for functional NER, is significantly reduced by treatment with CSC while the abundance of XPA protein, also required for NER, is unaffected. Both XPC and XPA RNA levels are modestly reduced by CSC treatment. Finally, treatment of cells with MG-132 abrogates the reduction in the abundance of XPC protein produced by treatment with CSC, suggesting that CSC enhances proteasome-dependent turnover of the protein that is mediated by ubiquitination. Together, these findings indicate that tobacco smoke can inhibit the same DNA repair pathway that is also essential for the removal of some of the carcinogenic DNA damage introduced by smoke itself, increasing the DNA damage burden of cells exposed to tobacco smoke.
Highlights
Lung cancer is a deadly disease and a leading cause of cancer-related mortality in the US and in the world [1,2,3]
These findings indicate that tobacco smoke can inhibit the same DNA repair pathway that is essential for the removal of some of the carcinogenic DNA damage introduced by smoke itself, increasing the DNA damage burden of cells exposed to tobacco smoke
We find that cigarette smoke condensate, a surrogate for tobacco smoke exposure, can inhibit nucleotide excision repair (NER) function and reduce the expression of XPC, a key protein required for DNA damage recognition in the NER pathway
Summary
Lung cancer is a deadly disease and a leading cause of cancer-related mortality in the US and in the world [1,2,3]. Exposure to tobacco smoke is the predominant risk factor for the development of lung cancer and it is estimated to account for 85–90% of all lung cancer cases [6, 7]. It is associated with the formation of tumors at additional sites in the body that are not directly exposed to smoke including the bladder, pancreas, liver, stomach and bone marrow [8, 9]. Lung cancer and other forms of cancer associated with tobacco smoke exposure remain a tremendous health burden in the US and world-wide. Continued elucidation of the molecular mechanisms that lead to the formation of cancers associated with tobacco smoke is essential for prevention, treatment and identification of individuals who are at greatest risk for the development of cancer
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