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Modelling telomere shortening and the role of oxidative stress

Lookup NU author(s): Dr Carole Proctor, Emeritus Professor Thomas Kirkwood

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Abstract

Extensive evidence supports the idea that progressive telomere loss contributes to the phenomenon of cell replicative senescence, but the mechanisms responsible for telomere loss are still unclear. In addition to the widely recognized end-replication problem, there is evidence that oxidative stress plays a major role in determining the rate of loss of telomeric DNA, and the action of a C-strand-specific exonuclease is also suggested to be important. We describe a mathematical model which examines the different contributions of these mechanisms to telomere loss and its role in triggering cell senescence. The model allows us to make quantitative predictions about the rates of telomere loss resulting from these alternative mechanisms, and their interactions. By varying the key parameters of the model, it is possible to examine the extent to which the different hypotheses are compatible with quantitative and qualititative features of the experimental data. For example, the model predicts that under low levels of oxidative stress, the main mechanisms of telomere shortening are the end-replication problem plus C-strand processing. However, when levels of oxidative stress are higher, as in cell cultures grown under normoxic or hyperoxic conditions, the model predicts that single strand breaks make an important contribution to telomere loss and their inclusion within the model is necessary to explain the data. We suggest that theoretical models of this kind are valuable tools to bridge the gap between the verbal statements of hypotheses and their rigorous experimental test. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

Publication metadata

Author(s): Proctor CJ, Kirkwood TBL

Publication type: Article

Publication status: Published

Journal: Mechanisms of Ageing and Development

Year: 2002

Volume: 123

Issue: 4

Pages: 351-363

Print publication date: 01/01/2002

ISSN (print): 0047-6374

ISSN (electronic): 1872-6216

Publisher: Elsevier Ireland Ltd

URL: http://dx.doi.org/10.1016/S0047-6374(01)00380-3

DOI: 10.1016/S0047-6374(01)00380-3

PubMed id: 11744046

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