Researchers at the National Institute on Aging (NIA) have found that the protein (WRNp) defective in the premature aging disorder, Werner's Syndrome (WS), forms a stable molecular complex with two proteins known to be involved in DNA repair, Ku70 and Ku86. The researchers found that the Ku (pronounced koo) proteins stimulate an enzymatic activity of the Werner protein that trims and degrades DNA ends, a process that is important to the repair of DNA breaks. This insight will lead scientists to explore the mechanism involved in DNA repair in Werner's Syndrome, which will help them to understand why DNA repair becomes less efficient during normal human aging.
The research, conducted by Drs. Vilhelm Bohr, Marcus P. Cooper, Robert Brosh, and colleagues at the NIA, with collaborators at the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill, is reported in the April 15, 2000 issue of Genes and Development .
"This finding adds an interesting twist to the understanding of Werner's Syndrome," said Dr. Vilhelm Bohr, NIA's Chief of the Laboratory of Molecular Genetics and principal investigator of the study. "One theory of aging suggests that DNA damage increases with age, either as oxidative DNA lesions or breaks in the DNA, and our finding relates to the repair of breaks. This work suggests that Ku and Werner proteins operate in the same molecular pathway."
Werner's Syndrome, a rare genetic disorder, causes people to appear much older than their chronological age, have a shortened lifespan, and to develop age-associated diseases including arteriosclerosis, cancer, diabetes, and osteoporosis in early adulthood. Individuals with WS begin to grow gray hair as teenagers, and develop cataracts, wrinkled skin, and thinning bones in their 20s. Most people with WS die in their 40s from cancer or heart attacks. WS has been considered a model of human aging, because the syndrome's symptoms mimic certain aspects of the aging process.
The gene responsible for WS (known as WRN) produces an enzyme thought to be involved in DNA metabolism (Yu et al., Science 4/12/96) . "Cells taken from patients with WS have many defects observed in normal aging," said Dr. Marcus P. Cooper. "It is important to elucidate the functions of the Werner protein as it may explain these defects."
Ku proteins are also involved in several DNA-related processes, notably the repair of double strand breaks in DNA, introduced, for example, by X-ray and chemotherapy. Researchers use knock-out mouse models, where a specific gene is removed to observe what difference its absence makes. When investigators delete the Ku protein gene in mice, the mice age prematurely, but it had not been clear how Ku worked in the aging process. Dr. Bohr's work could explain this since Werner and Ku proteins have now been shown to function in the same molecular pathways.
The next step, said Dr. Bohr, is to learn more about the WRN and Ku proteins' common molecular pathway and to identify other proteins that may bind to WRNp. "Explaining the interactions between the Werner and Ku proteins will contribute to the understanding of the causes of premature aging symptoms, and shed light on our understanding of the normal human aging process," said Dr. Bohr.
The National Institute on Aging, one of the 25 Institutes which make up the National Institutes of Health, leads the Federal effort supporting basic, clinical, epidemiological and social research on aging and the special needs of older people. For more information about the NIA, visit the website at www.nia.nih.gov .