28 January 2013
ByAppeared in BioNews 690
Scientists have for the first time shown the existence of a new structural form of DNA, called G-quadruplex DNA, in human cells. The four-stranded complexes are found to be most abundant in the chromosomes and telomeres of cells when they are about to divide, indicating a possible new target for cancer treatment.
'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, whose team led the study.
'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 personalised treatments in the future'.
Although the existence of G-quadruplexes has been shown in computational models and in laboratory experiments over the last ten years, this is the first time they have been identified in human cells. Thought to exist in transitory form as the cell divides, G-quadruplexes are found in regions of DNA rich in the molecule guanine, one of the four basic building blocks of DNA.
Computational analysis has shown that guanine-rich regions are often associated with telomeres, found at the tips of our chromosomes, protecting them from degradation or fusion with other chromosomes. They can also be found in regulatory regions of genes, called promoters.
In order to track the formation of these quadruplexes during the cell cycle, the scientists developed a protein antibody capable of binding only to G-quadruplex DNA and tagged it with a fluorescent marker, allowing them to differentiate it from normal double-stranded DNA.
The lowest levels of G-quadruplexes were observed during the first phase of the cell cycle, a stage where the cells rest before committing to a new cell division. A nearly three-fold increase was observed early in the replication stage, peaking at nearly five-fold increase during synthesis of new DNA. Blocking DNA replication led to a two-fold decrease in the number of complexes, indicating a strong link between DNA replication and formation of the G-quadruplex complexes.
'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', said Julie Sharp of Cancer Research UK, which funded the research.
An initial study by the same research team has identified a synthetic molecule, pyridostatin, than can stabilise these complexes and interfere with cell division.
It also remains to be seen if these complexes play a role in regulating cell division or occur just by chance. 'We plan to find out whether the quadruplexes are a natural nuisance, or there by design', Professor Balasubramanian said, adding: 'The possibility that particular cancer cells harbouring genes with these motifs can now be targeted, and appear to be more vulnerable to interference than normal cells, is a thrilling prospect'.