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Mortality Molecules

Svislo/istockphoto

Credit: Svislo/istockphoto

By Tracy Bryan

Cancer cells become immortal by exploiting a mechanism that protects normal cells from DNA damage. Can we use these molecules to turn off cancer’s fountain of youth?

Our genomes are subjected to a plethora of potentially damaging insults over the course of our lifetimes. Oxidative damage, irradiation, chemicals, and errors that occur when the genome is copied during cell division can lead to nicks, breaks and other damage to DNA.

Cells have evolved various “sensor” molecules to respond to this DNA damage, leading to either repair of the damage or cellular “suicide” if the damage cannot be repaired. This is an important safeguard that helps to prevent our normal cells from becoming cancerous.

In cancer cells, however, these responses to DNA damage are often defective, leading to the accumulation of mutations that can promote cancer cell division. We now know that cancer cells have yet another trick up their sleeve – they can also exploit these DNA damage-signalling molecules to keep the ends of their chromosomes long, essentially endowing themselves with immortal life.

The aspect of cell biology that has most fascinated me for the past 20 years is the process by which normal cells sense the fact that they are ageing. The ends of our chromosomes, known as “telomeres”, gradually shorten with each cell division over time. This process acts like an elegant biological “clock” that tells the cells of our body to age.

However, cancer cells counteract this clock and keep growing out of control. They use an enzyme called telomerase to reset the timer over and over again by adding telomeric DNA to the ends of chromosomes.

Telomerase was first discovered in 1985 by Australian scientist Elizabeth Blackburn and her graduate student Carol Greider in their laboratory at the University of California. They were awarded the Nobel Prize for this discovery in 2009. Interestingly, their initial discovery did not involve cancer cells or even human cells – they discovered telomerase in a single-celled pond organism. It was found almost a decade later that most cancer cells use an identical process to keep dividing indefinitely.

The research in my laboratory at Children’s Medical Research Institute is directed at understanding more about how telomerase works so that ultimately we can devise ways of blocking it as a future cancer therapy. One of the questions we have been addressing in recent years is to ask how telomerase gets to where it needs to go in the cell – the telomere.

It turns out that this is an incredibly complex process, but we have been able to get a handle on the problem by introducing a fluorescently labelled DNA probe into the cells. This probe is designed to seek out telomeres, where it can be visualised as fluorescently coloured dots under a microscope. We then introduce another probe that’s labelled with a different fluorescent colour. This second probe recognises telomerase. When we see overlapping dots of the two colours, we know that telomerase has reached the telomere (Fig. 1). These events can then be quantified.

Two key DNA damage-signalling proteins that are widely conserved throughout evolution are known as ATM and ATR. These proteins are necessary for telomerase to reach telomeres in yeast, but there were conflicting results regarding their involvement in this process in mammalian cells.

In experiments started by PhD student Josh Stern in our lab, we found that ATM is indeed necessary for telomerase to reach the telomeres in human cells. When Josh depleted the amount of ATM in cells, the overlapping dots representing telomerase dramatically disappeared from the telomere.

This was an exciting finding, but Josh was about to wrap up his PhD studies and head to the USA for postdoctoral work so another student, Adrian Tong, took over the project. Adrian carried out an enormous amount of experimental work over the course of his PhD, and was successful in figuring out many of the molecular details of this process.

ATM is a type of protein known as a “kinase”, and its function is to add a phosphate molecule to other proteins. This phosphate can then change the function of the protein it is attached to. Adrian’s first task was to determine which protein was receiving a phosphate from ATM during the process of telomerase recruitment to the telomere.

A good candidate was the protein TRF1, an integral structural component of telomeres. The laboratory of Prof Xu-Dong Zhu at McMaster University in Canada had already shown that ATM was able to add a phosphate to TRF1. Adrian collaborated with Prof Zhu’s lab and showed that this was the key event in telomerase recruitment. When ATM adds a phosphate to TRF1, this causes TRF1 to fall off the telomere, which in turn allows telomerase access to the telomere.

TRF1 is not normally used by ATM to respond to other types of DNA damage, so cancer cells are stacking the odds in their favour by exploiting the way that normal cells protect themselves against DNA damage, and using it to turn themselves immortal.

In other experiments, Adrian discovered that ATR, a close relative of ATM, is also involved in telomerase recruitment but in a different way. ATR responds to problems that occur during the process of DNA copying; one of its functions is to detect when there are “road blocks” interfering with the DNA replication machinery.

We found that if road blocks occur during the copying of telomeres, ATR reacts by bringing telomerase to telomeres. We speculate that this signal ensures that telomerase is brought to the telomere immediately after it has been replicated. This is therefore a second way that cancer cells are using a normal cellular response to DNA damage to ensure that their telomeres remain long.

These findings had the potential to be controversial, given the previous contradictory data between yeast and mammalian cells. We were therefore thrilled to learn that, using a different and complementary technique, the laboratory of Carol Greider, now a Professor at Johns Hopkins University, had also found that ATM is necessary for human telomerase to elongate telomeres. Both studies were recently published back-to-back in the journal Cell Reports (http://tinyurl.com/z87oy3w).

A majority of human cancers rely on telomerase for their continued growth. The new findings mean that new cancer treatments under development, some aimed at impairing telomerase function and others aimed at ATM, might show an even greater anti-cancer effect if they are used together. We are currently testing this possibility.

But cancer cells are not the only human cells that need telomerase. Most of the cells in an adult human body do not contain detectable amounts of telomerase, but it is relatively abundant in egg and sperm cells and in embryonic tissues in order to “reset” telomere length for the next generation. It’s likely that ATM is also required to recruit telomerase to telomeres in these cells, which partly explains the observation of short telomeres in the ATM-deficient cells of ataxia telangiectasia patients, who have impaired brain function, signs of premature ageing, and increased risk of certain types of cancers.

It’s likely that more surprises are in store as we and others unravel the complex links between telomere maintenance and the protection of the rest of the genome. This is likely to increase our understanding of the process of ageing, as well as how cancer cells subvert this process to achieve immortality.


A/Prof Tracy Bryan is Unit Head of the Cell Biology Unit at the Children’s Medical Research Institute.