A mathematical model of cellular apoptosis and senescence through the dynamics of telomere loss

Arkus, Natalie

doi:10.1016/j.jtbi.2004.12.016

Cited by 45 publications

(41 citation statements)

References 25 publications

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“…This is due to shortening of the chromosomal "tail," or telomere-a TTAGGG repeat sequence on the end of each chromosome. The loss of the telomere signals a break in the DNA sequence, resulting in dormancy and cellular senescence, or apoptosis, via the DNA damage response pathway [15]. This process does not affect post-mitotic neurons, but is important for neural stem cells and for supporting brain tissues.…”

Section: Intrinsic Arcsmentioning

confidence: 99%

Rethinking Alzheimer’s disease: The role of age-related changes

Drachman

2007

Curr Neurol Neurosci Rep

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Section: Intrinsic Arcsmentioning

confidence: 99%

Rethinking Alzheimer’s disease: The role of age-related changes

Drachman

2007

Curr Neurol Neurosci Rep

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“…Generate a random number T from the probability density function P T ðτ; aÞ defined below and set the time when the next reaction occurs to t þ T. P T ðτ; aÞ ¼ a expð−aτÞ ð0 ≤ τ < ∞Þ; [16] a ¼ ∑ 2. Set the length of every telomere i at time t þ T to l i ðtÞ þ ρT ð1 − A i ðtÞÞ.…”

Section: Methodsmentioning

confidence: 99%

“…If we use an average telomere length of 10 kbp and a binding site length of 12 bp, then there are approximately 833 binding sites, a number that is probably smaller, because the presence of histones most likely hides an important number of them. Meanwhile, there are approximately 2 million copies of TRF2 in the nucleus (16). Given this disparity between the concentrations of TRF2 and binding sites, in Eq.…”

Section: Deterministic Modelmentioning

confidence: 99%

Quantitative theory of telomere length regulation and cellular senescence

Rodriguez-Brenes

Peskin

2010

Proc. Natl. Acad. Sci. U.S.A.

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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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“…Critical telomere shortening causes chromosome destabilization and loss of telom ere functions, fusion of chromosome ends and attach ment of random DNA fragments to the chromosome ends. The cell responds to such chromosomal impair ments by activation of the DNA damage response sys tem resulting in activation of apoptotic processes and cell death [2,3].…”

Section: Introductionmentioning

confidence: 99%

The influence of compound aITEL1296 on telomerase activity and growth of cancer cells

Kovalenko

Zhdanov

Bibikova

et al. 2012

Biochem. Moscow Suppl. Ser. B

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Telomerase is a ribonucleoprotein complex, which synthesizes telomeric repeats and which has been identified as a promising target for anticancer therapy. Here we have investigated the effect of a new compound aITEL1296 on telomerase activity. aITEL1296 effectively inhibited telomerase activity; its inhib itory activity was a bit higher (IC 50 = 0.19 ± 0.02 ng/mL) than that of BIBR1532, one of the most potent telomerase inhibitors known to date. In addition to telomerase inhibition aITEL1296 activated apoptotic mechanisms and effectively suppressed proliferation of tumor cell lines (GI 50 = 5.0 ± 0.2 ng/mL for most sensitive cell line LnCap) but not normal fibroblast cell line.

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A mathematical model of cellular apoptosis and senescence through the dynamics of telomere loss

Cited by 45 publications

References 25 publications

Rethinking Alzheimer’s disease: The role of age-related changes

Rethinking Alzheimer’s disease: The role of age-related changes

Quantitative theory of telomere length regulation and cellular senescence

The influence of compound aITEL1296 on telomerase activity and growth of cancer cells

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