Living by the Code, a painting by Annie Newman in Shankar Balasubramaniam’s office, captures four-stranded DNA

Sixty years after James Watson and Francis Crick established that DNA forms a double helix, a quadruple-stranded DNA helix has turned up.

Quadruple helices that intertwine four, rather than two, DNA strands had been made in the laboratory, but were regarded as curiosities as there was no evidence that they existed in nature. Now, they have been identified in a range of human cancer cells.

The four-stranded packages of DNA, dubbed G-quadruplexes, are formed by the interaction of four guanine bases that together form a square. They appear to be transitory structures, and were most abundant when cells were poised to divide. They appeared in the core of chromosomes and also in telomeres, the caps on the tips of chromosomes that protect them from damage.

Because cancer cells divide so rapidly, and often have defects in their telomeres, the quadruple helix might be a feature unique to cancer cells. If so, any treatments that target them will not harm healthy cells.


“I hope our discovery challenges the dogma that we really understand DNA structure because Watson and Crick solved it in 1953,” says Shankar Balasubramanian of the University of Cambridge, UK.

Tagged with antibodies

Balasubramanian’s team identified the four-stranded structures in cancer cells with the help of an antibody that attaches exclusively to G-quadruplexes. To stop them from unravelling into the ordinary DNA, they exposed the cells to pyridostatin, a molecule that traps quadruple helices wherever they form.

This enabled the researchers to count how many formed at each stage of cell multiplication. The G-quadruplexes were most abundant in the “S-phase” – when cells replicate their DNA just prior to dividing.

“I expect they will also exist in normal cells, but I predict that there will be differences with cancer cells,” says Balasubramanian. His hunch is that the G-quadruplexes are triggered into action by chaotic genomic mutations and reorganisations typical of cancerous or precancerous cells.

“This research further highlights the potential for exploiting these unusual DNA structures to beat cancer, and the next part of this is to figure out how to target them in tumour cells,” says Julie Sharp of Cancer Research UK, which funded the research.

Another important question that Balasubramanian’s and other teams will try to answer is whether G-quadruplexes play a role in embryo development, and whether such a role is mistakenly reactivated in cancer cells. “We plan to find out whether the quaduplexes are a natural nuisance, or there by design,” he says.

Journal reference: Nature Chemistry, DOI: 10.1038/NCHEM.1548