Environmental Factor, December 2009, National Institute of Environmental Health Sciences
Chromium Linked to Telomere Damage
By Laura Hall
On November 10, Patricia Opresko, Ph.D., an assistant professor at the University of Pittsburgh, presented "Links Between Telomere Instability, Environmental Genotoxins and Human Disease" for the Keystone Science Lecture Series at NIEHS. Opresko is an NIEHS 2006 Outstanding New Environmental Scientist (ONES) grantee. ONES is a program that funds early career scientists for five years to investigate the influence of the environment on human disease. Opresko's research focuses on understanding telomere biology and the mechanisms of telomere loss.
During her talk, Opresko discussed telomere biology, the role of Werner syndrome helicase protein (WRN) and the deleterious effects of hexavalent chromium, Cr(VI), on telomeres. Human exposure to Cr(VI) occurs mainly as an occupational hazard in the welding industry where exposure is associated with respiratory problems and increased risk of lung disease. Cr(VI) is also found in pigments, anti-corrosive agents and sometimes at toxic waste sites.
Opresko explained that a telomere is a series of repetitive DNA elements at the end of a chromosome. Telomeres become shortened with each cell division, partly due to the inability of the DNA replicating enzyme to copy DNA at the tip of the telomere. Opresko said that this shortening mechanism normally limits the number of times cells can divide and this process is believed to be responsible for cellular aging and a limited lifespan. Sperm, egg and stem cells have an enzyme called telomerase that replaces the lost telomere sequence, while other cells of the body, called the somatic cells, do not show telomerase activity.
Fu-Jun Liu, Ph.D., a postodoctoral associate in Opresko's lab, has looked at the effects of the environmental pollutant Cr(VI) and found that it causes replicative stress chromosome breaks due to replication or stalling fork breaks (see Environmental Factor article(http://www.niehs.nih.gov/news/newsletter/2009/october/science-protective.cfm)). WRN, which unwinds and separates double-strand DNA allowing the DNA to be copied or repaired, is involved in the recovery from this Cr(VI) damage.
These studies are "the first molecular evidence that WRN protects against replicative stress induced by environmental pollutants," said Opresko. "I think this is a real strength of the ONES program and the NIEHS strategic plan, to try to use environmental agents to inform about biological pathways."
In addition, Opresko and Liu found that Cr(VI) exposure causes telomere damage. Guanine residues of the telomeric repeats are particularly susceptible to oxidative stress caused by Cr(VI). The studies show that Cr(VI) induces chromatid breaks, telomere defects and telomere loss. Cr(VI) induces telomeric defects presumably by interfering with telomeric replication.
In Werner syndrome, a premature aging disease caused by mutations in the WRN gene, the number of sister chromatid exchanges increases relative to normal and is confined specifically to the telomeres. WRN appears to play a role in preventing exchanges, by regulating the recombination of the telomeres. Opresko is currently conducting studies to investigate if Cr(VI) exposure induces more telomeric defects in cells lacking WRN.
The research on Cr(VI) and telomere damage has led Opresko to examine the mutagenesis rate of replicating telomeres using an assay she generated in her lab. Opresko has found that under normal conditions this rate is very low. She plans to use this system to see which proteins are important in telomere replication.
Understanding the role and interactions of the genetic and environmental factors that affect telomere biology may help scientists understand aging and diseases such as Werner syndrome. Doing so may also help to identify groups or individuals that may particularly be at risk from certain occupational or other environmental exposures.
(Laura Hall is a biologist in the NIEHS Laboratory of Pharmacology currently on detail as a writer for the Environmental Factor.)