Mini reviewTelomeres and replicative senescence: is it only length that counts?
Section snippets
Introduction: replicative senescence in primary human cell culture
Replicative senescence as first described for human fibroblasts [1] is the permanent loss of replicative potential, which is rather independent on culture time (however, see Ref. [2]) but occurs after a more or less constant number of cell divisions (‘Hayflick limit’) under constant culture conditions. In contrast to quiescence, the senescent cell arrest is stable in human cells. On the other hand, senescent cells stay alive for many months and are not preferentially sensitive to inducers of
Telomeres trigger replicative senescence
There are three principal, widely confirmed observations to support the hypothesis that telomeres are the replicometer, which counts cell divisions and ultimately triggers replicative senescence: First, telomeres shorten with each population doubling in primary human cell cultures but stop shortening in non-dividing cells [15], [16], [17]. Second, immortal cells, being it single cell organisms, germ line cells or tumour cells express in their vast majority active telomerase, the enzyme that
How does telomere length trigger replicative senescence?
Still, the signalling pathway(s) from shortened telomeres to induction of replicative senescence are largely unknown. In yeast, silencing trans-acting factors like SIR3 and SIR4 are part of telomeric heterochromatin and repress telomere-adjacent genes as they spread along the chromosome [27]. In theory, de-repression of these genes due to telomere shortening could activate cell cycle blockers. However, experimental evidence for this mechanism to contribute to replicative senescence in human
Does a threshold telomere length trigger replicative senescence?
It became almost a dogma in telomere research that a certain threshold telomere length is the trigger for replicative senescence. However, what does that mean? Is this threshold the same in different human cells or at least in different human fibroblast strains? Does it apply to the average length of all telomeres, to the length of the shortest telomere, to the length of a marker telomere (whatever this might be) or to the average length of a group of telomeres (e.g. the shortest)?
Conclusions
Telomeres are well established as the major replicometer, counting the number of cell divisions and eventually signalling replicative senescence in primary human cell strains. However, this does not mean that the pace of this biological clock is constant. Rather, telomere shortening is largely dependent on the interplay of oxidative stress/antioxidant defence [12], [13], [40]. Moreover, there is no inert threshold length at which senescence is triggered. Rather, the telomeric loop seems able to
Acknowledgements
Work from my group of relevance for this review has been supported by grants from the Deutsche Forschungsgemeinschaft, the VERUM Foundation for Behaviour and Environment, and the Newcastle Hospital Special Trustees Fund.
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