Telomere Dynamics and Cell Proliferation
E.H. Goodwin, S.M. Bailey, C.K. Sanders, and K.B. Blagoev
Los Alamos National Laboratory, Bioscience Division, Mail Stop M888, Los Alamos, NM 87545, USA
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.
Key words:
telomere, senescence, ALT
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