Elizabeth Blackburn inaugurates EACR 21st meeting and gives a broader outlook on these enzymes.

By Silvia Camporesi

The classic perspective on telomerases, which sees these enzymes as “bricklayers”, constant and repetitive enzymes deputed to the protection of chromosomes capping by adding DNA sequence repeats at the end of chromosomes, needs to be updated. With these words Dr Elizabeth Blackburn, 2009 Nobel laureate in Medicine (shared with Carol W. Greider and Jack W. Szostak) inaugurated the EACR 21^st meeting in Oslo. Since April 2010 Dr Blackburn is also President of the  American Association Cancer Research (AACR), which was yesterday referred to as the “sister association” of the European Association for Cancer Research (EACR) by the EACR President Anne-Lise Børresen-Dale, gladly keeping for once a (North) European centric perspective.

As other functions of telomerase are emerging, we need to scrutinize them more in depth and start considering these enzymes not only as simple labourers, but more as managers with the task of orchestrating and co-ordinating different tasks(at least, in mammalian cells).

On the one hand, lentiviral-expressed siRNA directed against telomerases show a rapid effect on human melanoma cells, as the work perfomed in the group led by Blackburn demonstrates (Bagheri et al, 2006). These effects amount to increasing melanin production and enhancing cell differentiation. Upon transduction, melanoma cells display a more differentiated and less invasive phenotype. The number of metastasis is also reduced, as demonstrated by the injection of two human melanoma cell lines in mice.  These findings indicate that telomerase exerts its proinvasive and prometastatic effects not solely by polymerizing telomeric DNA to elongate chromosome ends, but also through involvement in central cell fate decisions (Bagheri et al, 2006).

On the other hand, data obtained by Dr Blackburn's collaborators in Stanford show a striking phenotype in mice, which exibit a furry (hairy) phenotype upon overexpression of telomerases (Sarin KY et al, 2009). Conditional transgenic induction of telomerase in mouse skin epithelium causes a rapid transition from the resting phase of the hair follicle cycle to the active phase, by causing proliferation of quiescent, multipotent stem cells in the hair follicle bulge region. To note, this new function  does not require the telomerase RNA component -which encodes the template for telomere addition- and therefore operates through a novel mechanism independent of its activity in synthesizing telomere repeats.

These data indicate that, in addition to its established role in extending telomeres, telomerase can promote proliferation of resting stem cells through a non-canonical pathway, and fits within the “manager-orchestrating” view described by Dr Blackburn. These new function of telomerase could have potential therapeutic applications. For one, the suppression of the level of the telomerase ribonucleoprotein complex may have a place in therapies directed against advanced metastatic cancer, as the data by Bagheri and coauthors seem to indicate.

It seems therefore that we may soon have to come up with a new name for these multifaceted enzymes, which are obviously not only devoted to cap the ends (“telos”) of chromosomes and protecting their integrity, but also play a role that needs to be further elucidated in progenitor and stem cells. Suggestions are welcome!

References

Bagheri S, Nosrati M, Li S, et al. Genes and pathways downstream of telomerase in melanoma metastasis. PNAS 2006 ;103(30):11306-11.

Sarin KY, Cheung P, Gilison D, et al. Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 2005;436(7053):1048-52.

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