Fresh twist to the DNA story signals major cancer breakthrough

Crucial discovery at Cambridge, 60 years after Crick and Watson's double helix

The DNA double helix has been an icon of science ever since it was first described by Francis Crick and James Watson in 1953.

But now researchers have found that human DNA can naturally wrap itself into a different shape – a quadruple helix – in a breakthrough that could point the way to new cancer treatments.

The new structure, which is composed of four strands wrapped around each other, was confirmed by scientists from Cambridge University – the place where Crick and Watson made their famous discovery.

The quadruple DNA helix appears to be more common in cells that are rapidly dividing, indicating that it could be important in determining whether or not a cell becomes cancerous.

Professor Shankar Balasubramanian, who led the study published in the journal Nature Chemistry, said: "It is quite a distinct structure to the double helix. It's a beautiful four-stranded helix that we know little about, but we are convinced it exists naturally.

"The quadruple helix DNA structure may well be the key to new ways of selectively inhibiting the proliferation of cancer cells. The confirmation of its existence in human cells is a real landmark.

"We are seeing links between trapping the quadruplexes with molecules and the ability to stop cells dividing, which is hugely exciting. The research indicates that quadruplexes are more likely to occur in genes of cells that are rapidly dividing, such as cancer cells."

The DNA double helix was one of the greatest discoveries in science because it laid the foundations for understanding how genetic information is passed from one generation to the next, and how this information controls the biochemistry of the body.

Although scientists had known that DNA could form other unusual structures in the laboratory under artificial conditions, this is the first time that scientists have been able to show that it also forms a quadruple helix within living human cells.

Dr Julie Sharp, the senior science information officer at Cancer Research UK, which helped fund the work, said: "It's been 60 years since its structure was solved but work like this shows us that the story of DNA continues to twist and turn.

"This research further highlights the potential for exploiting these unusual DNA structures to beat cancer. The next part of the pipeline is to figure out how to target them in tumour cells."

The huge DNA molecule contains all the genetic information necessary to make a human being, encoded in the sequence of four chemical units or "bases", abbreviated as C, G, A and T, that make up the primary molecular structure of the chromosomes.

Professor Balasubramanian and his colleagues discovered that when there is a high proportion of the guanine base, the G unit, the double helix breaks down into the quadruple form, which forms a tight knot within the DNA molecule.

When the scientists used small drug-like molecules to trap these quadruplex structures, they discovered that they could interfere with the process of cell division, suggesting that the quad helix is somehow involved in the replication of cells – and hence the uncontrolled replication seen in cancers.

"We have found that by trapping the quadruplex DNA with synthetic molecules we can sequester and stabilise them, providing important insights into how we might grind cell division to a halt," Professor Balasubramanian said. "There is a lot we don't know yet. One thought is that these quadruplex structures might be a bit of a nuisance during DNA replication, like knots or tangles that form… The possibility that particular cells harbouring genes with these motifs can now be targeted, and appear to be more vulnerable to interference than normal cells, is a thrilling prospect."

The paper is available to read online here.

Life in brief: the scientist

Shankar Balasubramanian was born in Madras (now Chennai), India, in 1966 and came to Britain with his parents a year later. He grew up just outside Runcorn in Cheshire where he attended local schools.

He graduated from Cambridge University in 1988 and stayed on to do his PhD. He is now the Herchel Smith Professor of Medicinal Chemistry and also works at the Cambridge Research Institute – a collaboration between the university and the charity Cancer Research UK. He was elected a Fellow of the Royal Society last year.

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