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Modelling the regulation of telomere length: the effects of telomerase and G-quadruplex stabilising drugs

Telomeres are guanine-rich sequences at the end of chromosomes which shorten during each replication event and trigger cell cycle arrest and/or controlled death (apoptosis) when reaching a threshold length. The enzyme telomerase replenishes the ends of telomeres and thus prolongs the life span of ce...

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Autores principales: Hirt, Bartholomäus V., Wattis, Jonathan A. D., Preston, Simon P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975128/
https://www.ncbi.nlm.nih.gov/pubmed/23620229
http://dx.doi.org/10.1007/s00285-013-0678-2
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author Hirt, Bartholomäus V.
Wattis, Jonathan A. D.
Preston, Simon P.
author_facet Hirt, Bartholomäus V.
Wattis, Jonathan A. D.
Preston, Simon P.
author_sort Hirt, Bartholomäus V.
collection PubMed
description Telomeres are guanine-rich sequences at the end of chromosomes which shorten during each replication event and trigger cell cycle arrest and/or controlled death (apoptosis) when reaching a threshold length. The enzyme telomerase replenishes the ends of telomeres and thus prolongs the life span of cells, but also causes cellular immortalisation in human cancer. G-quadruplex (G4) stabilising drugs are a potential anticancer treatment which work by changing the molecular structure of telomeres to inhibit the activity of telomerase. We investigate the dynamics of telomere length in different conformational states, namely t-loops, G-quadruplex structures and those being elongated by telomerase. By formulating deterministic differential equation models we study the effects of various levels of both telomerase and concentrations of a G4-stabilising drug on the distribution of telomere lengths, and analyse how these effects evolve over large numbers of cell generations. As well as calculating numerical solutions, we use quasicontinuum methods to approximate the behaviour of the system over time, and predict the shape of the telomere length distribution. We find those telomerase and G4-concentrations where telomere length maintenance is successfully regulated. Excessively high levels of telomerase lead to continuous telomere lengthening, whereas large concentrations of the drug lead to progressive telomere erosion. Furthermore, our models predict a positively skewed distribution of telomere lengths, that is, telomeres accumulate over lengths shorter than the mean telomere length at equilibrium. Our model results for telomere length distributions of telomerase-positive cells in drug-free assays are in good agreement with the limited amount of experimental data available.
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spelling pubmed-39751282014-04-07 Modelling the regulation of telomere length: the effects of telomerase and G-quadruplex stabilising drugs Hirt, Bartholomäus V. Wattis, Jonathan A. D. Preston, Simon P. J Math Biol Article Telomeres are guanine-rich sequences at the end of chromosomes which shorten during each replication event and trigger cell cycle arrest and/or controlled death (apoptosis) when reaching a threshold length. The enzyme telomerase replenishes the ends of telomeres and thus prolongs the life span of cells, but also causes cellular immortalisation in human cancer. G-quadruplex (G4) stabilising drugs are a potential anticancer treatment which work by changing the molecular structure of telomeres to inhibit the activity of telomerase. We investigate the dynamics of telomere length in different conformational states, namely t-loops, G-quadruplex structures and those being elongated by telomerase. By formulating deterministic differential equation models we study the effects of various levels of both telomerase and concentrations of a G4-stabilising drug on the distribution of telomere lengths, and analyse how these effects evolve over large numbers of cell generations. As well as calculating numerical solutions, we use quasicontinuum methods to approximate the behaviour of the system over time, and predict the shape of the telomere length distribution. We find those telomerase and G4-concentrations where telomere length maintenance is successfully regulated. Excessively high levels of telomerase lead to continuous telomere lengthening, whereas large concentrations of the drug lead to progressive telomere erosion. Furthermore, our models predict a positively skewed distribution of telomere lengths, that is, telomeres accumulate over lengths shorter than the mean telomere length at equilibrium. Our model results for telomere length distributions of telomerase-positive cells in drug-free assays are in good agreement with the limited amount of experimental data available. Springer Berlin Heidelberg 2013-04-26 2014 /pmc/articles/PMC3975128/ /pubmed/23620229 http://dx.doi.org/10.1007/s00285-013-0678-2 Text en © The Author(s) 2013 https://creativecommons.org/licenses/by/2.0/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Article
Hirt, Bartholomäus V.
Wattis, Jonathan A. D.
Preston, Simon P.
Modelling the regulation of telomere length: the effects of telomerase and G-quadruplex stabilising drugs
title Modelling the regulation of telomere length: the effects of telomerase and G-quadruplex stabilising drugs
title_full Modelling the regulation of telomere length: the effects of telomerase and G-quadruplex stabilising drugs
title_fullStr Modelling the regulation of telomere length: the effects of telomerase and G-quadruplex stabilising drugs
title_full_unstemmed Modelling the regulation of telomere length: the effects of telomerase and G-quadruplex stabilising drugs
title_short Modelling the regulation of telomere length: the effects of telomerase and G-quadruplex stabilising drugs
title_sort modelling the regulation of telomere length: the effects of telomerase and g-quadruplex stabilising drugs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975128/
https://www.ncbi.nlm.nih.gov/pubmed/23620229
http://dx.doi.org/10.1007/s00285-013-0678-2
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