Insight: Research Edition

Fall 2006

Scientists Show How Telomeres Affect Cancer Risk

Dr. Susan Bailey studies the images gaily lighting up her computer screen and notes the total state of disarray. In bright reds, yellows and greens, this picture of chromosomes may look beautiful, but it shows a system that is failing to protect the most basic structure of life – the genome.

In humans, as well as in every other eukaryotic organism (organisms with a complex cell or cells), chromosomes are arranged in a linear fashion. The physical ends of the chromosomes, or telomeres (literally meaning “end-part”) were first described by scientists almost 70 years ago based on the telomere’s end-protection function. Telomeres consist of highly repetitive DNA that preserves chromosomal stability, including protecting the ends of chromosomes from degradation and preventing chromosomal ends from improperly fusing. Every time the cell divides, the telomere erodes a little bit so that over time, with aging, exposure to carcinogens, or genetic disease, telomeres shorten and eventually malfunction. Telomeres can be extended by telomerases, a specialized enzyme involved in the synthesis of telomeres. Telomerase, however, is active only in germ line and stem cells, and certain white blood cells, but is repressed in most cells of the body. A notable exception is cancer cells, where high telomerase activity creates “immortal” cells, capable of dividing forever (which is why they can form tumors).

“We are investigating relationships between DNA repair and telomere biology – specifically we are looking at the role of dysfunctional telomeres in carcinogenesis,” said Dr. Bailey, an Assistant Professor in the Department of Environmental and Radiological Health Sciences and investigator with the Cancer Biology Group. “Through the Flint Animal Cancer Center (ACC), we have the opportunity to evaluate canine tumors and determine telomere length and telomerase status, which are more similar to human than the mouse, thus using dogs as a model for human cancer to better understand the role telomeres play in the development of cancer.”

When telomeres aren’t functioning properly, researchers see rearrangement and misjoining of chromosomes. This chromosome instability can contribute to increased cancer risk. Also, some individuals are more prone to chromosomal instability than others. From a practical point of view, understanding this vulnerability and how it impacts DNA repair capability may help these people make better decisions regarding exposures to carcinogens and cancer therapy options.

Understanding telomerase and telomeres, said Dr. Bailey, will not only help to define risk; it will also help to develop more refined treatments of cancer.

“Telomerase is very active in cancer cells, with the vast majority of tumors being telomerase positive,” said Dr. Bailey. “By developing telomerase inhibitors, we may be able to target cancer cells specifically. Combining this strategy with reducing DNA repair may speed up the process and kill tumors faster. This is a very exciting area of research.”

Working with many collaborators over the years, including Dr. Maria A. Blasco, a researcher in Spain who developed the telomerase knock-out mouse, Dr. Bailey and her team continue to examine telomere function and carcinogenesis. Dr. Bailey is working with Drs. Sue Lana and Kelvin Kow at the ACC on canine osteosarcomas. She is establishing collaborative efforts with researchers in the lab of Dr. Thomas Cech at the University of Colorado’s Health Sciences Center. Her research team works closely with Dr. Robert Ullrich’s (Department of Environmental and Radiological Health Sciences) laboratory and is currently examining the role of telomeric proteins in the DNA damage response in collaboration with Dr. Jacob A. Aten, a researcher in the Netherlands. Her team is examining the role of telomere instability in human breast cancer, collaborating with Dr. Alice Sigurdson of the Radiation Epidemiology Branch of the National Cancer Institute. They also are modeling the role of telomeric vs. genomic recombination in collaboration with Dr. Edwin H. Goodwin of Los Alamos National Laboratory. Dr. Bailey’s work on mouse Pot1, in collaboration with Dr. Sandy Chang at the M.D. Anderson Cancer Center, was recently accepted for publication in Cell.