When Watson and Crick discovered the double helix structure of DNA in 1953, they declared they had “found the secret of life”. However, as in all pursuits of science, the story did not end there. Less than 60 years later, a team led by chemist Professor Shankar Balasubramanian and cancer biologist Professor Steve Jackson has found that an unusual four-stranded configuration of DNA also forms at sites across the human genome in living cells.
Although known about by scientists for decades, the structure was considered to be something of a structural curiosity rather than a feature found in nature. It forms in regions of DNA that are rich in one of its building blocks, guanine (G), when a single strand of the double-stranded DNA loops out and doubles back on itself, forming a four-stranded ‘handle’ in the genome.
G-quadruplexes have been known to occur at the ends of chromosomes in the regions known as telomeres, but it wasn’t until a strong association had been noticed with genes responsible for cell proliferation that Balasubramanian and others began to suspect that G-quadruplexes might be a potential target for cancer therapy. “If you synthesise a quadruplex-binding molecule and put it into cancer cells, it can impair the growth of these cells,” he said. “We’ve come such a long way from thinking that we understand the genome – and it appeared that this structure could tell us something new.”
Dr Raphaël Rodriguez, a Senior Research Associate who has worked with Balasubramanian for the past seven years, developed a small synthetic drug called pyridostatin to target G-quadruplexes. Two years ago the pair joined forces with Jackson, whose lab is studying the fundamental biology of cancer. In a recent article published in Nature Chemical Biology, they showed that not only do these structures form in cancer cells – the first time this has been demonstrated – but that pyridostatin can actually interact with G-quadruplexes to prevent proliferation of these cells. Although the function of G-quadruplexes remains a mystery, the discovery holds great potential for new, more selective approaches to treating cancer via interference with the genome, as well as offering a new dimension to personalised medicine.
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Image: G-quadruplex DNA Credit: Jean Paul Rodriguez
Reproduced courtesy of the University of Cambridge
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