Quantitative theory of telomere length regulation and cellular senescence

Abstract

In normal somatic cells, telomere length shortens with each cell replication. This progressive shortening is associated with cellular senescence and 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 also the onset of senescence. One hypothesis is that the t loop, a large lariat-like structure, represents the capped state. In this paper we model a telomere state on the basis of the biophysics of t-loop formation, allowing us to develop a single mathematical model that accounts for two processes: telomere length regulation for telomerase positive cells and cellular senescence in somatic cells. The model predicts the steady-state length distribution for telomerase positive cells, describes the time evolution of telomere length, and computes the life span of a cell line on the basis of the levels of TRF2 and telomerase expression. The model reproduces a wide range of experimental behavior and fits data from immortal cell lines (HeLa S3 and 293T) and somatic cells (human diploid fibroblasts) well. We conclude that the t loop as the capped state is a quantitatively reasonable model of telomere length regulation and cellular senescence. mathematical model | telomerase | telomeres T elomeres are noncoding repetitive sequences of DNA at the end of the chromosomes of eukaryotic cells. They play an important role in "hiding" the end of the chromosomes from the DNA damage response pathway. Dysfunctional telomeres may be interpreted as DNA breaks that may lead to nonhomologous end joining and may trigger senescence or apoptosis through the p53 and p16-RB pathways (1, 2).Because of the linear nature of eukaryotic DNA and the unidirectional synthesis of DNA polymerases, normal human somatic cells are unable to replicate their DNA completely (3). It is also believed that telomeres are actively degraded by an unknown exonuclease (4). These processes together with the action of oxidative stress (5) result in the progressive shortening of telomeres. Both in vivo and in vitro telomere lengths correlate with cellular life span.Germ cells, stem cells, and cancer cells (in approximately 85% of cancer types) express telomerase, an enzyme that extends telomere length (6). Cells that express telomerase at sufficient levels maintain a stable telomere length and have an unlimited replication capacity (7). Furthermore, it has been shown that the introduction of telomerase into normal human cells can extend the life span of a cell culture (8).The function and dynamics of telomeres depend on the action of several proteins that interact with chromosome ends. Particular attention has been given to shelterin, a complex of six telomere-specific proteins that protect and reshape telomeres (9). A key feature of shelterin is its ability...

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