Quadruple-helix DNA found in human cells, eyed to beat cancer

Sixty years after Cambridge researchers published a paper on the double-helix DNA as the chemical code of life, another group of Cambridge researchers has published a paper proving the existence of quarduple-helix, four-stranded, DNA structures. The paper indicates the quadruple helix structures, known as G-quadruplexes, form in DNA regions rich in the building block guanine and can potentially head off cancer, Phys.org reported. Researchers believe targeting quadruplexes with synthetic molecules that trap and contain these DNA structures – thus preventing cells from replicating their DNA and consequently blocking cell division – may help halt runaway cell proliferation at the root of cancer. "We are seeing links between trapping the quadruplexes with molecules and the ability to stop cells dividing, which is hugely exciting," said Professor Shankar Balasubramanian from the University of Cambridge's Department of Chemistry and Cambridge Research Institute. "The research indicates that quadruplexes are more likely to occur in genes of cells that are rapidly dividing, such as cancer cells. For us, it strongly supports a new paradigm to be investigated – using these four-stranded structures as targets for personalized treatments in the future," Balasubramanian added. Phys.org said these findings culminate 10 years of scientists' efforts to show these complex structures in vivo or living human cells. The research, published in Nature Chemistry and funded by Cancer Research UK, showed "clear links" between concentrations of four-stranded quadruplexes and the process of DNA replication, which it said is key to cell division and production. Test tube Phys.org said studies in the last couple of decades had showed quadruplex DNA can form in vitro, or the test tube. But now, the researchers know they actually form in the DNA of human cells. "This research further highlights the potential for exploiting these unusual DNA structures to beat cancer – the next part of this pipeline is to figure out how to target them in tumor cells," said Dr. Julie Sharp, senior science information manager at Cancer Research UK. "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," she added. Antibody proteins The study was led by Giulia Biffi, a researcher in Balasubramaninan's lab at the Cambridge Research Institute. Biffi built on previous research and generated antibody proteins that detect and bind to areas in a human genome rich in quadruplex-structured DNA. This proved their existence in living human cells. Also, the researchers used fluorescence to mark the antibodies so they could identify hot spots for the occurrence of four-stranded DNA, both where in the genome and at what stage of cell division. "While quadruplex DNA is found fairly consistently throughout the genome of human cells and their division cycles, a marked increase was shown when the fluorescent staining grew more intense during the 's-phase' - the point in a cell cycle where DNA replicates before the cell divides," Phys.org said. It noted cancers are usually driven by genes called oncogenes that have mutated to increase DNA replication – causing cell proliferation to spiral out of control, and leading to tumor growth. The increased DNA replication rate in oncogenes leads to an intensity in the quadruplex structures, meaning potentially damaging cellular activity can be targeted with synthetic molecules or other forms of treatments. "We have found that by trapping the quadruplex DNA with synthetic molecules we can sequester and stabilize them, providing important insights into how we might grind cell division to a halt," said Balasubramanian. Yet, Balasubramanian said there still much they do not know yet. One thought is that these quadruplex structures might be a sort of nuisance during DNA replication, like knots or tangles. "Did they evolve for a function? It's a philosophical question as to whether they are there by design or not – but they exist and nature has to deal with them. Maybe by targeting them we are contributing to the disruption they cause," Balasubramanian said. The study showed that if an inhibitor is used to block DNA replication, quadruplex levels go down, proving the idea that DNA is dynamic. Also, the researchers found an overactive gene with higher levels of Quadruplex DNA is more vulnerable to external interference. "The data supports the idea that certain cancer genes can be usefully interfered with by small molecules designed to bind specific DNA sequences," said Balasubramanian. Balasubramanian said many current cancer treatments attack DNA, but it's not clear what the rules are. "The possibility that particular cancer cells harboring genes with these motifs can now be targeted, and appear to be more vulnerable to interference than normal cells, is a thrilling prospect. 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," Balasubramanian said. — LBG, GMA News