Cell biology

Shaggy mouse tales

First impressions can be misleading. The enzyme telomerase has been well studied because of its initial association with cell ageing processes and cancer — but it now seems that this is not all it can do.

The way in which a biological entity is first identified can limit perceptions of the full range of its functions. The telomerase enzyme, for instance, was originally discovered on the basis of its vital ability to lengthen telomeres — the stretches of non-coding DNA at the ends of chromosomes. If it is too short, a telomere loses the ability to maintain a protective structure at the end of the chromosome, and such shortened telomeres can signal to cells to cease multiplying, in a process called cellular senescence. In this issue, Sarin et al. (page 1048)1 report provocative evidence that telomerase does more than merely synthesize DNA at chromosome ends: a key subunit of the enzyme stimulates the proliferation of mouse hair-follicle stem cells, generating shaggy mice. Strikingly, this occurs independently of the DNA-synthesis capacity of telomerase.

Telomerase adds DNA to the tips of the chromosomes to replenish the telomeres. This DNA would otherwise dwindle away as cells multiply, owing to incomplete replication of the chromosomal DNA and to enzymes nibbling away at the DNA end regions. In normal human cells, telomerase is highly regulated, and its efficiency depends, among other things, on the cell type2. The enzyme is present in very low amounts in most cultured human primary cells (that is, those grown directly from biopsies)3, so their telomeres gradually shorten and the cells senesce. If such cultured cells are made to express excessive amounts of normal telomerase, the telomeres elongate and overcome cellular senescence, so the cells continue to multiply.

Telomerase is actually a complex of molecules, and its DNA-synthesis function requires a collaboration between two core components, a protein subunit called TERT and an RNA component called TERC in mice. To explore the function of TERT, Sarin and colleagues made a mouse strain that contained an extra TERT gene; the original TERT gene was left intact. The extra gene had a control element so that it could be turned on or off at will in the live animal. When switched on, the gene produced large amounts of TERT protein in all cells of the animal's body.

The authors found that when TERT was overexpressed in this way the mice were very furry, and that this was due to increased proliferation of hair-follicle stem cells. A similar effect was independently reported recently for TERT overexpressed only in mouse skin4. These stem cells produce the mature follicles from which hair grows, and the extent of their proliferation controls fur growth. The authors next timed the TERT overexpression to occur at specific periods in the cycling of the hair follicles between their active (anagen) and resting (telogen) stages. They found that the overexpressed TERT could reawaken telogen hair follicles, causing them to move into the anagen phase and promoting hair growth. Most remarkably, the prolific hair growth was apparent even when the TERT gene was overexpressed in a mouse strain that lacked the RNA component of telomerase (Fig. 1), showing that the effects on hair growth are independent of the DNA-synthesis function.

Figure 1: Telomerase is more than it seemed.
figure1

The telomerase enzyme was first discovered based on its ability to add DNA to the telomere regions at the ends of chromosomes. It works as a complex with two core components: the protein TERT and an RNA component called TERC in mice. However, Sarin et al.1 find that TERT can also stimulate the proliferation of hair-follicle stem cells and hair growth — even in the absence of TERC. Perhaps other functions of telomerase have yet to be found.

How might the core-protein subunit of telomerase make mice shaggy in the complete absence of its function of telomeric DNA synthesis? The answer is unclear. Evidence that telomerase has additional biological roles began to surface in the late 1990s, through experiments on the enzyme in yeast and human cells5. Certain partially active mutant forms of telomerase were found to overcome cellular senescence despite massive shortening of the telomeres; the cells continued to multiply even though their telomeres were shorter than those normally seen in senescent cells5. In addition, overexpressing normal telomerase in cultured human primary cells changed the patterns of gene expression across the whole genome, whereas cell growth rates and overall telomere length did not change noticeably6. Moreover, reducing even the small amount of functional telomerase in normal human fibroblasts (connective-tissue cells) accelerates their senescence7. Even before their telomeres shorten, this quickly compromises normal protective cellular responses to agents that damage DNA3.

Human cancer cells commonly have high telomerase activity, although their telomeres are typically short. However, blocking telomerase production rapidly inhibits cancer-cell growth without telomere shortening, and alters the cells' gene-expression profile in a distinctive fashion that may be associated with diminished cancer progression8. Indeed, an in vivo model of skin cancer showed that inhibiting production of the telomerase RNA reduced metastasis9. Although certain cells lacking telomerase can maintain their telomeres by an alternative mechanism, which is independent of telomerase, the tumour-generating capacity of such cells is less than that of cells expressing telomerase10. Conversely, overexpressing TERT in mice promotes early progression of skin cancer4.

How all these effects are mediated, and whether or how they involve telomerase activity on or off the telomere, are unknown. TERT is known to form at least one complex without telomerase RNA — yeast TERT binds to a protein called PinX1 in a manner that is mutually exclusive of its binding to telomerase RNA11. So perhaps TERT forms other complexes with as-yet-unidentified partners.

In ancient Egypt, men smeared their pates with hippopotamus fat in a desperate bid to stave off baldness12. Is telomerase the new hippopotamus fat? Probably not. But this enzyme is already known to be vital in sustaining tissues in health and disease, and we should look beyond its eponymous function to understand the full spectrum of its potential roles.

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Blackburn, E. Shaggy mouse tales. Nature 436, 922–923 (2005). https://doi.org/10.1038/436922a

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