New Scholar Award in Aging
David K. Orren, Ph. D.
University of Kentucky Chandler Medical Center

Understanding the Role of Genomic Instability in Human Aging: The Paradigm of the Premature Aging Disease Werner Syndrome

Throughout life, our DNA is constantly subject to damage from both environmental agents and endogenous reactive oxygen species. Due to incomplete repair of this damage, changes in DNA accumulate in each cell as time passes. Such changes (mutations) are known to have a role in the etiology of cancer, and are thought to be involved in the manifestation of other characteristics of normal human aging.

The notion that changes in DNA are related to the process of aging has been bolstered by recent characterization of the molecular defect in the hereditary disease Werner syndrome (WS). Individuals with WS have early onset of many characteristics of normal aging including graying and loss of hair, wrinkling and ulceration of the skin, and increased frequency of many age-related diseases including cancer, atherosclerosis, diabetes, cataracts, and osteoporosis. Cells from WS patients show elevated chromosomal abnormalities (mostly deletions and translocations), accelerated loss of telomeric sequences, and premature cellular senescence. Intriguingly, this wide range of organismal and cellular abnormalities is apparently the result of defects in a single gene, WRN. The demonstation of helicase and exonuclease activities inherent in purified WRN protein by several laboratories (including ours) indicates that WRN is involved in some aspect of DNA metabolism. Thus, a lack of functional WRN protein somehow disrupts the maintenance of DNA, leading to chromosomal abnormalities, accelerated telomere shortening, loss of cellular replicative capacity, and early onset of aging characteristics.

Our laboratory has been investigating the interactions of purified WRN protein with other proteins and with model DNA substrates. We recently have shown that WRN interacts physically with the Ku heterodimer and, in the process, markedly stimulates the exonuclease activity of WRN. The Ku heterodimer has established roles in V(D)J recombination and double-strand break repair and a potential role in telomere metabolism. Like WRN-deficient cells, Ku-deficient cells have elevated genomic instability and undergo premature replicative senescence. The functional interaction of WRN with Ku suggests a possible role for WRN in double-strand break repair and/or telomere maintenance. Our future studies will be directed at investigating and defining the potential roles of WRN in these pathways.

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