New clues to the secret of eternal life

Some of the mystery surrounding ageing, death and cancer is dispelled by a major new study in the premier journal Cell¹.

Scientists from Cancer Research UK and Breast Cancer Campaign have uncovered the first evidence of an entirely new system for holding the ravages of time at bay.

The system involves adding thimble-like caps to the ends of chromosomes in order to protect DNA from damage and slow the ageing process.

Cancer cells may rely on DNA capping for their remarkable ability to grow and divide eternally – ignoring the normal constraints on lifespan. The discovery could provide a new route of attack for up to 10 per cent of tumours.

Each human cell has an inbuilt timer to ensure it lives as long as necessary and no longer. Attached to the ends of the chromosomes (the packages of genetic material within cells) are repetitive strips of DNA called telomeres. These get shorter each time a cell divides until there is nothing left – and the cell knows it is time to die.

But cancer cells are immortal – they are able to reset or stop their timer, giving them unlimited lifespan. Many cancer cells do this by using an enzyme called telomerase to rebuild their telomeres, but researchers knew this couldn’t be the only culprit, since cancer cells can achieve immortality without it.

In the new study, scientists at the Cancer Research UK London Research Institute, with additional funding from Breast Cancer Campaign, investigated how else cancer cells might subvert the natural ageing process.

They used a technique called immunofluorescence to light up various molecules within cancer cells and see precisely where they were operating. One particular molecule, called RAD51D, appeared time and again at the site of the telomeres, suggesting it was interacting in some way with the timer mechanism.

When researchers blocked the activity of RAD51D using a second technique called RNA interference, they found substantial damage to the telomeres and other parts of the genome – the telltale signs of accelerated ageing.

RAD51D is known to play a role in repairing DNA, but the authors suggest that is has a second role – as supplier of a protective cap for the telomeres.

Dr Madalena Tarsounas, leading the study at the Cancer Research UK London Research Institute and funded by both Breast Cancer Campaign and Cancer Research UK, says: “Cancer has an amazing ability to shake off the shackles of ageing and death, which is one of the reasons why it can be so hard to treat.

“Understanding how cancer cells remain eternally young has been a key focus of research for more than a decade, so it’s particularly exciting to have made such a striking discovery.

“We have found evidence of a completely new mechanism for stopping the clock on a cancer cell’s timer and preventing its lifespan from ticking down. It raises the possibility of starting the clock again and making cancer cells susceptible to death once more.”

Having a stable telomere is important to prevent a cell’s genetic material from becoming unstable. Researchers believe that in normal cells, RAD51D may stabilise the telomeres without interfering with the timer that limits their lifespan. But in cancer cells RAD51D may be over-active, stopping the clock and allowing the cells to grow and divide indefinitely.

Drugs to block the action of RAD51D could potentially be effective against many different tumours, by stripping cancer cells of their immortality.

Dr Tarsounas adds: “We think as many as 10 per cent of tumours may be heavily reliant on the new mechanism to keep their cells alive and these may also be highly susceptible to drugs targeted against it.

“As well as opening the way to new types of treatment for cancer, our study has shed light on the complex but intriguing processes which control how and when we get old.”

Pamela Goldberg, Chief Executive of Breast Cancer Campaign, says: “By avoiding one of the normally inescapable cell mechanisms, cell death, cancer cells are able to have unique control in the human body. This research has discovered an important element which appears to be essential in sidestepping this cell death process and if we can in some way control this we may be able to stop the growth and spread of cancer cells.”

Professor Robert Souhami, Cancer Research UK’s Director of Clinical and External Affairs, says: “Ageing, at least at a cellular level, isn’t just a question of running out of steam but a carefully planned process to keep the number of old and new cells in balance.

“Cancer cells are adept at slipping the constraints of the ageing process, but this highly significant study points to ways of making them mortal, and vulnerable, once more.”

ENDS

1. Cell117 pp.337-347