Computer Simulation of Telomere Dynamics and Senescence
K.B. Blagoev, E.H. Goodwin
Los Alamos National Laboratory, Theoretical Division, Mail Stop B262, Los Alamos, NM 87545, USA
In normal human somatic cells, telomeres become shorter with each cell
cycle until their chromosome end protection function fails causing the
cells to senesce. Previously telomere loss was thought to be gradual,
and the approach to cellular senescence was likened to a mitotic clock
in which the shortest telomere of a progenitor cell determined the
maximum number of cell doublings. In addition to the basal loss,
recent evidence indicates that there are occasional large gains, losses
and exchanges of telomeric DNA collectively called telomere dynamics.
We are using discrete Monte Carlo computer simulations to explore the
dependence of cellular proliferation on telomere dynamics. This work
clearly shows that, when telomere lengths vary stochastically, a
deterministic mitotic clock is an inadequate model of cellular
proliferation. Compared to predictions of the mitotic clock model,
senescent cells appear much earlier in simulated colony growth, just as
they do in real cultures, and the cause of senescence is not
necessarily the shortest initial telomere. Interestingly because of
the stochastic nature of telomere dynamics, two indistinguishable
progenitor cells may go through quite different colony growth
experiences. The methods used to construct these simulations, and
insights gained from them, will be presented in detail.
Key words:
modeling, telomere dynamics, Monte Carlo
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