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Unexpected Consequences of Telomere and Telomerase Dysfunction

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There are fundamental aspects of telomere and telomerase biology that are widely accepted and known to play key roles in the ageing process.

Telomeres have long been known to play a key role in preventing the ends of our chromosomes from being recognised as damage and eliciting a cell cycle arrest. ...

There are fundamental aspects of telomere and telomerase biology that are widely accepted and known to play key roles in the ageing process.

Telomeres have long been known to play a key role in preventing the ends of our chromosomes from being recognised as damage and eliciting a cell cycle arrest. Telomerase, a reverse transcriptase, is capable of replenishing telomeres through the action of its catalytic unit (Tert) and RNA template (Terc). Due to restricted telomerase expression in most human cells and the end-replication problem, telomeres shorten with cell divisions throughout our lifespan. In fact, telomere dysfunction is a hallmark of ageing, and progressive telomere dysfunction is a major player in the impairment of tissue homeostasis with age in a cell-autonomous manner, by impaired proliferation, and in a non-cell-autonomous manner, by accumulation of senescent cells in tissues, which can be exacerbated in telomerase deficient models and human progerias.

However, compelling data suggest that both telomerase and telomeres may have unexpected functions in different cell types, and these potential “non-canonical” functions may in turn affect disease and the ageing process independently or in combination with their canonical function. Telomerase has other functions besides telomere elongation and telomeres may also have other roles besides protecting the ends of linear chromosomes. For example, telomerase has been shown to modulate transcription of genes involved in a wide variety of cellular functions, from DNA repair, to enhanced proliferation, inhibition of apoptosis and enhanced migration, and altered differentiation, including in unexpected cell types such as immune myeloid cells. Less is known about the non-canonical functions of telomerase in the context of ageing and, in particular, in immune cells. This is partly due to the difficulty in distinguishing phenotypes caused by telomerase absence per se from telomere shortening. Moreover, and much less explored are potential “non-canonical” functions of telomeres. For example, telomeres have been described to be capable of modulate immune activation by actively interacting with intracellular Toll-like receptors. Additionally, through the regulation of TERRA, telomere length may also indirectly affect gene expression.

If we are to truly understand the role of telomeres and telomerase in health and disease throughout the lifecourse, it is imperative we start integrating and disentangling these unexpected, “non-canonical” functions, not only of telomerase, but also of telomeres themselves. This collection aims at collecting the most recent evidence of these phenomena, with the aim of providing a framework for future research and potential collaborations.


Keywords: telomere, telomerase, ageing, cell division, senescence


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