Quadruple helices that intertwine four, rather than two, DNA strands have been researched for decades. They have been made synthetically in the lab, but were seen only as curiosities as there was no evidence that they formed naturally. Now they have been identified in human cancer cells.
The four-stranded packages of DNA, called G-quadruplexes, are formed by the interaction of four guanine bases that together make a square. They appear to be transitory structures, and are most abundant when cells are poised to divide. They form in chromosomes and 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 lead researcher Shankar Balasubramanian of the University of Cambridge. "We need to be open about what its structure is, because it's dynamic."
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 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 division. The G-quadruplexes were most abundant in the "S-phase" - when cells replicate their DNA just before dividing (Nature Chemistry, doi.org/j9b).
"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 formation of G-quadruplexes is triggered by the 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 study.
Previous work carried out by the group found that the addition of pyridostatin to human breast cancer cells stopped them from replicating and from migrating across a gel in a process that mimics the spread of cancer cells in the body (Nature Chemical Biology, doi.org/j9f).
The results reinforce the possibility that blocking G-quadruplexes could combat cancers. "If you block them with pyridostatin, it's bad news for the cell," says Balasubramanian.
As well as determining whether quadruple helices exist in healthy cells, another important question 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 quadruplexes are a natural nuisance, or there by design," Balasubramanian says.
an article from New Scientist ma