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A DNA double helix

DNA is usually found as a double helix, but a rarer form may be involved in cancer

Think of DNA and you probably think of a double helix – the spiralling ladder shape made famous by Crick and Watson. But DNA can also exist in a number of other, rarer, forms.

Led by Professor Shankar Balasubramanian, scientists at our Cambridge Research Institute embarked on a molecular ‘fishing trip’ inside our cells. They found some rather unusual DNA structures known as G-quadruplexes – twisted bundles of DNA that are a far cry from the familiar double helix.

Published recently in the journal Nature Chemistry, not only does this work provide the first hard evidence that these structures exist in humans, but it also reveals a new avenue for future cancer treatments.

From double helix to quadruplex

Most of the time, the DNA in our cells exists as a twisted ladder made of two complementary strands.  This is known as a double helix.

But researchers have found that lengths of DNA containing long stretches of guanine – one of the four chemical ‘letters’ that make up the molecule – can fold up into unusual four-way structures known as G-quadruplexes.

Computer analysis suggests that the human genome contains plenty of regions of DNA that could form quadruplexes. Most notably, these crop up at telomeres – the ‘caps’ on the ends of chromosomes that prevent them from ‘fraying’ and protect us from cancer.

But until now, G-quadruplexes have only been detected in mixtures of DNA in test tubes or simple single-celled organisms, rather than living human cells.  So Professor Balasubramanian and his team set out to find them.

Preparing the ‘bait’

As with any fishing trip, the researchers first needed to make a ‘bait’. They started off with pyridostatin, a molecule that they knew could interfere with telomeres and was therefore likely to be attracted to any G-quadruplexes that might be present.

Next they added extra bits to pyridostatin, producing a molecule that stuck even more strongly to G-quadruplex DNA. They even added a ‘hook’, allowing them to rescue the bait – and anything attached to it – from any liquid.

The team then went fishing in a ‘soup’ made from mashed-up human cancer cells and  – reassuringly – the bait worked, specifically pulling out G-quadruplexes consisting of DNA from the cells’ telomeres.

In further experiments, they tested whether their bait molecule had any effects on living cells.  Intriguingly, the chemical slowed the growth of cancer cells grown in the lab, suggesting that it was interfering with their telomeres in some way and stopping them from dividing.

Hook, line and sinker

This work is important because it shows for the first time that G-quadruplex DNA exists in the telomeres of human cancer cells. But how is it linked to the disease?

Each time a healthy cell divides, the telomeres at the ends of its chromosomes (individual strands of DNA in the cell) get shorter and shorter. This means that cells can only divide a certain number of times before the ends of its chromosomes become frayed and ragged – it’s a deliberate mechanism to make sure our cells die a timely and dignified death, maintaining order in our bodies and preventing cancer developing.

But a key feature of cancer cells is that they somehow gain the ability to patch up their telomeres as they divide, allowing them to multiply indefinitely. So understanding more about telomeres – including their three-dimensional structure – could open up a new line of attack against cancer.

Indeed, researchers around the world –including Cancer Research UK-funded scientists such as Professor Stephen Neidle and Dr Duncan Baird – have been trying to unravel the secrets of our telomeres and use them against cancer. This latest research is another step on that road.

If G-quadruplexes exist at telomeres in the human cells tested by Balasubramanian and his team, then it’s possible that they also exist in cells in many – and quite possibly all – cancers. Thanks to their ‘bait’, the researchers now have a useful tool with which to study G-quadruplexes in human cells.

The team’s results also build on evidence from Professor Neidle and others, showing that drugs targeting G-quadruplexes could be useful for treating cancer.   At the moment this work is still at the lab stage, but this latest paper adds support to this potentially fruitful avenue of research.

Kat

Reference:

Müller, S. et al (2010). Small-molecule-mediated G-quadruplex isolation from human cells Nature Chemistry, 2 (12), 1095-1098 DOI: 10.1038/nchem.842

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