ComBio: Unravelling the subtleties of telomerase

The telomeres are intriguing repetitive structures found on the chromosome tips, which are responsible for preventing the gradual erosion of the ends of the chromosomes.

Critical to the mechanisms protecting telomeres is an enzyme called telomerase, a complicated ribonucleoprotein complex that adds telomeric repeat sequences to the ends of chromosomes that was first discovered by expatriate Australian researcher, Prof Elizabeth Blackburn, now at the University of California, San Francisco.

But while telomerase was initially discovered in the mid-1980s, it is only now that its mechanisms of action are being teased out. According to Blackburn, while there is a lot known about the enzyme, there is also a lot still to be learned, and its subtleties are only just coming to light.

The enzyme is part of an exquisitely regulated homeostatic system, with elaborate control by regulatory components, of which much is still unknown. Blackburn finds the consequences of the regulation of the system intriguing.

"Our passion is to understand how the hell a telomere really works," says Blackburn, who gave a plenary lecture at ComBio 2003. "It's a very robust system, designed to be resilient and self-correcting, and telomerase is just one component.

Blackburn says recent discoveries from familial genetic studies of the rare disease congenital dyskeratosis have underlined the importance of maintaining the genetic integrity of both copies of the telomerase RNA transcript gene, which provides both a template for addition of the telomere repeat sequence and catalytic functions.

"The RNA transcript was not initially thought to be an important rate limiting component [of telomerase], but now clinical work says that it is. You need both gene copies [of the RNA transcript gene] to get a full human lifespan," she says. At the heart of the matter is a dynamic RNA-RNA intermolecular pairing, but as yet, no one knows how it works.

Variations in the lengths of telomeres between humans have been correlated to variability in lifespan, and Blackburn believes that variations in the sequence of the telomerase RNA transcript may be one piece of the puzzle.

"There is a big genetic component to telomere length -- we'd like to find out what it is," she says. One of the variables is the sequence of the telomerase RNA transcript. While certain dominant mutations cause severely truncated human lifespans, other variations may have more subtle effects.

"We want to look at RNA variation in the population... in huge cohorts of well-studied populations," Blackburn says.

Blackburn is also interested in applying her knowledge of telomerase mechanisms to combat cancer. Tumour cells commonly show unregulated telomerase activity, and she has been investigating ways of switching the enzyme off, to allow the cell to die.

By changing the sequence of the telomerase repeat sequence, through knock-down strategies involving delivery of mutant templates to cells, the attachment of binding proteins to the telomeres can be abrogated, causing apoptosis in a p53 independent process. The research is still at an early stage, but Blackburn thinks there is promise for future therapeutics.

"Ideally it will be a small molecule that warps the RNA, like having a mutant template," she says.

Blackburn herself has managed to remain apart from the biotechnology industry, despite the interest in her research from the sector. More interested in the natural history aspects of telomere research, she is happy to leave the more applied research to others.

But while she says the initial hype surrounding telomeres as a potential modifier of lifespan was damped down by realisation of the complexities of the system, she believes that there are possibilities to exploit the system both as a therapy for diseases like cancer and to prolong human lifespans.