In quite a unique piece of research, Prof Shankar Balasubramanian from Cambridge’s department of chemistry has shown the first proof of the existence of quadruple helix DNA in human cells. The work was published in the journal Nature Chemistry on 20th January, 2013.
What is Quadruple Helix DNA?
G-quadruplexes (also known as G-tetrads or G4-DNA) are nucleic acid sequences that are rich in guanine and are capable of forming a four-stranded structure. The “G” here, refers to guanine, one of the four chemical groups, or “bases”, that hold the DNA together(the others being adenine, cytosine, and thymine). 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.
The protective tips of chromosomal DNA, known as telomeres, are rich in guanine and so are likely candidates for G-quadruplex structures. In fact, studies in cancer cells have shown that small molecules that bind and stabilize G-quadruplex structures cause DNA damage at telomeres, supporting the argument.After searching through human genome data in search of other such guanine-rich sequences, some researchers have suggested that quadruplexes could also be created in other areas of the genome involved in regulating genes, particularly some cancer-causing genes.
The DNA structure determined by Francis Crick, James Watson and others, often said to be the greatest discovery of the past century, had two long strands which wound together to form the complete genetic information needed to form and maintain our bodies. However, as in all pursuits of science, the story did not end there. Some 60 years later, the hunt to understand the complexities of the DNA continues on.
How did they do it?
To track the DNA G-quadruplex in the human cells, they generated an engineered, structure-specific antibody which would specifically tag and quantitatively visualize them via a fluorescence marker so that the time and place of the structures’ emergence in the cell cycle could be imaged.
Importance of the discovery?
As i said earlier, 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 it was noticed, G-quadruplexes might be a potential target for cancer therapy. One of the key differences between cancer cells and normal cells is cancer cells are generally more vulnerable to DNA-damaging drugs. With the small synthetic drug called pyridostatin, developed by Balasubramanian’s colleagues to target G-quadruplexes,more selective approaches to treating cancer via interference with the genome can be envisaged bringing on a new dimension to the field of personalised medicine.
- Small-molecule–induced DNA damage identifies alternative DNA structures in human genes, Shankar Balasubramanian, Nature Chemical Biology, 2012.
- G-quadruplex structures: in vivo evidence and function, Lipps, H. J. & Rhodes, D., Trends in Cell Biology, 2009.
- Prevalence of quadruplexes in the human genome, Huppert, J. L. & Balasubramanian, S, Nucleic Acids Research, 2005.
- In vitro generated antibodies specific for telomeric guanine-quadruplex DNA react with Stylonychia lemnae macronuclei, Schaffitzel, C. et al., Proceedings of National Academy of Sciences, 2001.
- A single-molecule platform for investigation of interactions between G-quadruplexes and small-molecule ligands, Koirala, D. et al., Nature Chemistry, 2011.