Skip to main content

Research Repository

See what's under the surface

Advanced Search

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.

Authors

Bartholomäus V. Hirt Barth.Hirt@gmx.net

Jonathan A.D. Wattis Jonathan.Wattis@nottingham.ac.uk

Simon P. Preston



Abstract

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.

Journal Article Type Article
Publication Date 2014-05
Journal Journal of Mathematical Biology
Print ISSN 0303-6812
Electronic ISSN 1432-1416
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 68
Issue 6
Pages 1521-1552
APA6 Citation Hirt, B. V., Wattis, J. A., & Preston, S. P. (2014). Modelling the regulation of telomere length: the effects of telomerase and G-quadruplex stabilising drugs. Journal of Mathematical Biology, 68(6), 1521-1552. https://doi.org/10.1007/s00285-013-0678-2
DOI https://doi.org/10.1007/s00285-013-0678-2
Publisher URL http://link.springer.com/article/10.1007%2Fs00285-013-0678-2
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

Files

Modelling the regulation of telomere length: the effects of telomerase and G-quadruplex stabilising drugs (1.1 Mb)
PDF

Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





You might also like



Downloadable Citations

;