Elsevier

Biochimie

Volume 90, Issue 1, January 2008, Pages 116-121
Biochimie

Review
Telomere dynamics in human cells

https://doi.org/10.1016/j.biochi.2007.08.003Get rights and content

Abstract

Human telomeres are intrinsically dynamic structures, with multiple biological processes operating to generate substantial length heterogeneity. Processes that operate specifically at the terminus, that include the end-replication problem coupled with C-strand resection, result in gradual telomere erosion with ongoing cell division. Rates of telomere erosion can be modulated by cell culture conditions and pleiotropic effects. Other processes, that are not consistent with the end replication problem, generate sporadic large-scale changes in telomere length. These events are detected in normal human cells and tissues; the severely truncated telomeres that result are potentially fusogenic and may lead to the types of genetic rearrangements that typify early-stage neoplasia. The processes that underlie sporadic telomeric deletion are unclear, but may include intra-allelic recombination within the T-loop structure, unequal sister chromatid exchange and replication fork stalling. The relative contributions of these processes in the generation of the heterogeneous telomere length profiles observed in human cells are discussed.

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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