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'.
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.
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'.