Program
| MSB2c | |
|---|---|
| Ignacio Rodriguez | |
| Courant Institute of Mathematical Sciences | |
| Title | A mathematical model of telomere length regulation and cellular senescence |
| Abstract | Telomeres play an essential role in chromosomal function and cell viability by preventing chromosome ends from being interpreted by the DNA damage response machinery as DNA breaks. In normal somatic cells telomere length shortens with each cell replication and correlates with the onset of senescence or apoptosis. Germ cells, stem cells and the majority of cancer cells express telomerase, an enzyme that extends telomere length and when expressed at sufficient levels can immortalize or extend the life span of a cell line. It is believed that telomeres switch between two states: capped and uncapped. The telomere state determines its accessibility to telomerase and the onset of senescence. One hypothesis is that the t-loop, a large lariat-like structure, represents the capped state. In this talk we present a model telomere state based on the biophysics of the t-loop and the effects of TRF2, a telomere binding protein implicated in t-loop formation. We provide a mathematical description of a telomere length sensing feedback loop for telomerase positive cells and a model of cellular senescence for normal somatic cells. The model predicts the steady state length for telomerase positive cells, describes the time evolution of telomere length, and computes telomere length and the life span of a cell line based on the levels of TRF2 and telomerase expression. By fitting the model to a variety of experimental data we show that a model of telomere length regulation and cellular senescence based on the t-loop is capable of replicating a wide range of experimental results. |
| Location | Friedman 153 |