Heterogeneity and Telomeres

One of the earlier suggestions to explain cell-to-cell heterogeneity was that telomere uncapping, the process that leads to telomeres being recognized as inducers of a DNA damage response triggering growth arrest, is itself stochastic (Blackburn 2000). While some random variation in uncapping remains a possibility, it is unclear that such an effect is sufficient to explain the observed heterogeneity in both telomere lengths and division capacity within cultures of cells.

In fact, there is good experimental evidence for large heterogeneity in telomere length, both between chromosome ends within individual cells and between cells. Interchromosomal variation in telomere length has been observed in cultured human hematopoietic cells by Q-FISH. Telomere fluorescence intensity values were found to vary up to six-fold per metaphase (Lansdorp et al. 1996). Zou et al. found that a specific subgroup of chromosomes displayed the shortest telomeres in near-senescent cells and that this subgroup induced a DNA damage response and replicative senescence (Zou et al. 2004). This is indicative that shortening of individual telomeres is not uniform in cells. It is, however, not clear yet whether such a subgroup is in itself a stochastic selection or whether there are factors that modulate telomere shortening in a chromosome-specific way.

The latter possibility has been suggested by Q-FISH analyses. Some studies indicated that intracellular, interchromosomal heterogeneity might be cell line- and donor-specific and heritable (Graakjaer et al. 2004). More studies using various methodological approaches and larger numbers of cells will be necessary to prove or disprove this point. Using STELA, a method able to measure telomere lengths from individual chromosomes, extensive cell-to-cell variation of telomere lengths on individual chromosome arms (e.g., the Xp/Yp chromosome) has been found (Baird et al. 2003), which seems to suggest a strong influence of nonheritable (chance) factors on telomere length heterogeneity. At present, the relative impact of heritable and randomly acting factors on inter- and intrachromosomal telomere length distributions cannot yet be conclusively estimated.

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