Abstract
Telomeres are a hotspot for sister chromatid exchange (T-SCE). Any biological consequence of this form of instability remained obscure until quantitative modeling revealed a link between elevated T-SCE rates and accelerated cellular replicative senescence. This work strongly suggests that progressive telomere erosion is not the only determinant of replicative capacity; instead, T-SCE need to be considered as an independent factor controlling colony growth and senescence. Additionally high T-SCE rates have been observed in cells with deficiencies in WRN and BLM, the genes that are defective in Werner's and Bloom's syndromes, implying a connection to premature aging. In this Research Perspective we will explore some of the implications this recent work has for human health.
Highlights
CO-FISH (Chromosome Orientation Fluorescence In situ Hybridization), a strand-specific modification of standard FISH invented in the early 1990s [1], is elegant in its simplicity and powerful in its application [2]
We began working with telomere probes early on as a means to determine the absolute 5’-to-3’ direction of DNA sequences within chromosomes, a capability that would be useful for orienting contigs at a time when the human genome was being sequenced for the first time [3]
Once we convinced ourselves the split was real and not an artifact, we settled on sister chromatid exchange (SCE) as the most likely cause; these events are referred to as telomere sister chromatid exchange (T-SCE)
Summary
A quick calculation revealed that telomeric DNA must be a hotspot for this kind of recombination. We surmised (incorrectly as it turned out) that during multiple exchanges occurring during colony expansion at least a few cells – the lucky winners in the exchange process – might maintain their telomeres well enough for the colony to escape senescence [4]. This recombination-based mechanism might explain alternative lengthening of telomeres (ALT), a mechanism used by some tumors to maintain telomeres in the absence of telomerase [5]. The losers – those cells inheriting the shorter sister telomeres – were placed at risk for entry into early senescence
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