Explainer: quadruple-helix dna

DNA has been called many things: the king of molecules, the blueprint of life, and less excitingly but perhaps more accurately, the genetic code. DNA’s double helix, discovered in 1953 by

James Watson and Francis Crick, is one of the most recognisable natural structures ever reported by scientists. And recently, nearly 60 years after Watson and Crick’s famous discovery, a

team of Cambridge researchers has confirmed the existence, in humans, of an alternate DNA structure: a G-quadruplex. To understand the significance of this discovery we need to understand a

little about DNA itself. SIMPLE COMPLEXITY The simplicity of DNA’s components and the spectacular complexity of the resulting organisms never cease to inspire a sense of wonder. All that’s

needed is just four “bases”, arranged into pairs – adenine and thymine, cytosine and guanine – and connected to two backbones which are wound tightly around each other. Only the number and

order of the bases determines the difference between single-celled bacteria and human life. Although the double helix is the most common and best known structure of DNA, this fascinating

molecule is capable of adopting many other structures, including a four-stranded helix. G-QUADRUPLEX Instead of pairs, sequences rich in guanine can form quartets consisting exclusively of

this base. Stacks of these guanine quartets form a quadruple helix, also known as a G-quadruplex. This discovery was made less than ten years after the publication of the double helix

structure but, until very recently, the existence of G-quadruplexes in human cells had not been proven. The fact that human DNA contains many guanine-rich sequences, and that these form

G-quadruplexes in a test tube, was considered to be indirect evidence for their existence in human cells. G-QUADRUPLEXES IN HUMANS The human genome contains approximately 376,000 sequences

with the potential to form G-quadruplexes. Their locations in the genome suggest they are more than a mere structural curiosity and fulfil important functions in the cell cycle. On January

20, a team of researchers at the University of Cambridge, led by Shankar Balasubramian, published a paper in Nature Chemistry showing strong evidence for the existence of G-quadruplexes in

human cells and their involvement in the replication of cells. To achieve this, the researchers produced antibodies that specifically recognise G-quadruplexes but no other DNA structures.

These antibodies were labelled with a fluorescent molecule that can be observed in a microscope, and used this to track the formation and location of G-quadruplex structures during the cell

cycle. The highest number of G-quadruplexes was observed in the S phase of the cell cycle – the point at which DNA is separated into two single strands and copied prior to cell division.

This observation suggests G-quadruplexes are important for cellular replication. EXCITING IMPLICATIONS This research also shows that the number of G-quadruplex structures present in human

cells can be increased by a small molecule called pyridostatin, which can stabilise G-quadruplexes in the test tube. This same molecule can also stop the growth of human cancer cells by

damaging parts of the DNA that are important for replication. There is still a long way to go towards unravelling the precise function of these quadruple helices but the findings discussed

here show a link between these structures and cellular replication. Further research to gain a better understanding of this link may eventually lead to insights into the mechanisms that

cause cancer and improved treatments.