Environmental Factor, October 2009, National Institute of Environmental Health Sciences
Investigators Show Protective Role of DNA Repair Protein
By Brian Chorley
A new NIEHS-supported study reports that human cells deficient in a singularly resourceful DNA repair enzyme, known as Werner syndrome protein (WRN), exhibit more replicative stress and DNA damage after exposure to the industrial pollutant hexavalent chromium - Cr(VI) - than do cells with normal WRN levels. The findings were published in Toxicological Sciences by Assistant Professor Patricia Opresko, Ph.D. (http://www.biophysics.pitt.edu/site/faculty_detail.php?id=30) , - a recipient of an NIEHS Outstanding New Environmental Scientist (ONES) award - and her research team in the Department of Environmental and Occupational Health at the University of Pittsburgh.
While the role of WRN malfunction in premature aging and cancer predisposition in individuals suffering from Werner syndrome is well documented, this study (http://www.ncbi.nlm.nih.gov/pubmed/19487340?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) provides the first molecular evidence of the protective effects of this DNA repair protein in Cr(VI) toxicity - as well as further evidence that Cr(VI) induces replicative stress and replication-associated DNA breaks. In their conclusion, the authors point to persistent public health concern about occupational exposure to Cr(VI) at levels below the permissible limit as reason why a complete understanding of its genotoxicity and carcinogenicity is so critical.
Cr(VI) is a chemical compound used commonly as an anti-corrosive agent and pigment in paint, dyes and other surface coatings. Melting metal chromium, which is a component of stainless steel, results in chromium oxidation and conversion to a hexavalent state. Industrial workers and others in the vicinity of these materials without protective gear can inhale and expose sensitive lung tissue to Cr(VI). Acute inflammation in nasal passages and conducting airways can result from high levels of short-term exposure. Chronic long-term exposure has been shown to significantly increase lung cancer risk.
The researchers explain that this increased cancer risk is thought to result from the reduced forms of Cr(VI) that are generated after cellular uptake of Cr(VI), which readily create DNA adducts and subsequent interference with DNA replication machinery. This interruption can lead to double-strand breaks, which contribute to genomic instability via chromosomal rearrangements, genomic deletion and other potentially detrimental mutational events.
Cells have evolved recovery mechanisms to resist genomic instability. WRN is a DNA helicase, which allows for proper DNA access and processing by DNA replication and repair enzymes. This role is underscored by the observation that individuals who lack the ability to produce WRN are predisposed to cancer development and premature aging, a condition known as Werner syndrome.
Opresko and her research team reasoned that WRN, given its role in DNA repair, would likely protect cells from Cr(VI)-induced toxicity. They demonstrated that WRN-deficient cells were hypersensitive to Cr(VI) and exhibited markers of double-strand breaks and stalled DNA replication machinery. While these markers of genomic instability were also observed in cells with normal levels of WRN protein, recovery occurred much later in WRN-deficient cells.
Opresko's observation is one of the few that describe how cells mechanistically resist Cr(VI) toxicity. Importantly, this information creates a more complete picture of how Cr(VI) contributes to cancer etiology. While the Cr(VI)-induced double-strand DNA breaks have been well described, exposure also overwhelms the processes of recovery and repair. This suggests that individuals with attenuated production of WRN, whether genetic or chemically altered, may be more susceptible to the detrimental effects of Cr(VI) exposure.
University of Pittsburgh Postdoctoral Associate Fu-Jun Liu, Ph.D., was first author on the study. It was also co-authored by University of Pittsburgh Associate Professor Aaron Barchowsky, Ph.D. (http://www.eoh.pitt.edu/personnelDetail.asp?pid=139&id=25&ptype=2&pnavcat=2) Funding for the study was provided by the Ellison Medical Foundation and an NIEHS grant (http://tools.niehs.nih.gov/portfolio/sc/detail.cfm?appl_id=7666812) for studies on "Mechanisms of Telomeric DNA Loss and Repair."
Citation: Liu FJ, Barchowsky A, Opresko PL. (http://www.ncbi.nlm.nih.gov/pubmed/19487340?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) 2009. The Werner syndrome protein functions in repair of Cr(VI)-induced replication-associated DNA damage. Toxicol Sci 110(2):307-318. Epub ahead of print.
(Brian Chorley, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Environmental Genomics Group.)