ReviewTelomere dynamics in human cells
Section snippets
The end replication problem and C-strand resection
Semi-conservative DNA replication presents a problem when it comes to fully replicating a linear DNA molecule. As originally pointed out by Alexi Olovikov in 1971 [1], the end replication problem results in a single-stranded loss of DNA at the lagging strand, whilst the leading strand can be fully replicated to create a blunt ended molecule. This assumes that DNA replication is initiated internally and proceeds towards the terminus, which appears valid as data from S. cerevisiae demonstrates
Allele/chromosome specific telomere length variation
Genome wide telomere length exhibits considerable variation in the human population; this is apparent from extensive cross sectional surveys in many different tissues, see for example [28]. Some of this variation will be generated by different rates of cellular turnover, which may be influenced by disease status and lifestyle [30], [31], [32], [33]. However it is also clear that telomere length variation is genetically determined [34], [35], such that individuals can start life with
Sporadic telomeric deletion
Detailed analysis of telomere dynamics in human cells has indicated the existence of additional mechanisms that generate sporadic large-scale changes in telomere length. Sporadic telomeric deletion is not consistent with end-replication losses [9], [46] and therefore probably involves additional mutational mechanisms. Early evidence for sporadic length changes in human cells came from studies in an experimentally transformed cell line carrying a tagged chromosome end, such that the dynamics of
Kinetics of growth in cell culture
Human cells in culture do not divide in synchrony, with faster growing clonal populations accounting disproportionately for the increase in the cell number [62], [63], [64]. This situation is very much exaggerated in Werner's syndrome fibroblasts, which when passaged in culture display a severely attenuated replicative lifespan, with the majority of cell growth being accounted for by successive expansions of single clonal populations [65], [66], [67]. Rates of telomere erosion are calculated by
Acknowledgements
D.M.B is a Cancer Research UK Senior Cancer Research Fellow.
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