Silence of the triple helix 14/02/07. By the Wellcome Trust A direct role for RNA in switching off a gene essential for cancer cell growth has been uncovered by researchers at the University of Oxford.

Dr Alexandre Akoulitchev, a Senior Research Fellow at the University of Oxford, and colleagues examined two DNA regions (promoters) that control whether the human dihydrofolate reductase gene is turned on or off.

The major promoter normally drives activity of the gene, but the researchers found that a non-coding RNA (an RNA that is not used to produce proteins) produced from the minor promoter could turn off gene activity by binding to the major promoter, forming a triple helix of DNA and RNA.

The dihydrofolate reductase gene needs to be active when cells are replicating, as it produces an enzyme that controls the production of thymine, a vital ingredient of DNA. A supply of thymine allows dividing cells to replicate their DNA, but when cells are not dividing, thymine is not required and the dihydrofolate gene is shut down.

As cancer cells divide rapidly and rely on a supply of thymine, the new discovery opens up the opportunity of using a non-coding RNA to inhibit the production of dihydrofolate reductase and stop cancer cells dividing. Methotrexate, the first anticancer drug, also acts by binding to and inhibiting this enzyme.

Non-coding RNAs are one of the current 'hot topics' in biology. In recent years they have been found to control the expression of genes in many different ways, but usually by interfering with the RNA produced from a gene, before it can be used to make a protein, or with the protein-production system itself.

Dr Akoulitchev and colleagues have now uncovered a new mechanism. In this case, the non-coding RNA shuts down the dihydrofolate reductase gene by interacting directly with its promoter and disrupting the binding of proteins that normally start expression.

The research was funded by the Wellcome Trust and the Medical Research Council.

Further reading

Martianov I et al. Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript. Nature 2007; 445(7128):666-70. Abstract

Links

Biochemistry of Nuclear Dynamics Research Group