E.H. Goodwin, S.M. Bailey, C.K. Sanders, and K.B. Blagoev

Telomere length changes are far more dynamic than previously thought. In addition to a gradual loss of ~100 base pairs per telomere in each cell division, large losses as well as gains may occur within a single cell cycle. How these processes, collectively referred to as telomere dynamics, influence cellular proliferation and the approach to senescence is poorly understood. We are investigating how telomere exchange, extension, and deletion affect the proliferative potential of telomerase-negative somatic cells. Experimental techniques are being devised to detect dynamic telomere processes, differentiate between them, and quantify both the frequency and length changes of each. In parallel, a 'dynamic telomere model' is being formulated that incorporates telomere dynamics. By simulating how the telomere size distribution evolves with time, we expect to learn how it controls important parameters of culture growth. This is an essential step towards understanding the role that telomere dynamics play in the normal aging and pathology of tissues and organisms. For example, the model will cast light on relationships not otherwise easily explained by a deterministic "mitotic clock", such as that between the senescent cell fraction and population doubling time, or to what extent the shortest initial telomere determines the onset of senescence. We also expect to identify biomarkers that will correlate with aging better than average telomere length. Additionally we hope to shed light on the transition to unlimited growth potential found in telomerase-negative tumor cells having the ALT (alternative lengthening of telomeres) phenotype, and to evaluate strategies to suppress the growth of these tumors.

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