Have you ever had a doubt about what exactly you can recycle? The cell is faced with the same problem when it encounters epigenetic nucleosides. It does not really know if they can be recycled as they are or discarded.
New research by the team of Skirmantas Kriaucionis shows that although such nucleotides are normally discarded, their recycling and incorporation into DNA in certain cancers constitutes a new therapeutically-exploitable avenue for cancer research.
Cells are pretty good at recycling material ingested from neighboring dying cells. This is especially true of nucleotides, through enzymes like cytidine deaminase (CDA), which participates in the recycling of deoxycytosine. Additionally, it maintains equilibrium between deoxycytosine and deoxyuracil, which provides the sole source of thymidine for the cell.
However, epigenetically-modified cytosine creates somewhat of a recycling dilemma (a bit like your mixed plastic/cardboard sandwich box) because the incorrect positioning of epigenetic modifications into DNA could have severe consequences for the cell.
Among these epigenetically-modified bases are the newcomers, 5-hydroxymethyldeoxycytosine (5hmC) and 5-formyldeoxycytosine (5fdC). After first having found that DNA polymerases cannot distinguish between these epigenetically-modified nucleotides and unmodified nucleotides when they are transfected into replicating cells, Kriaucionis and his team set out to understand what happens to the nucleosides 5-hydroxymethyldeoxycytidine (5hmdC) and 5-formyldeoxycytidine (5fdC) during nucleotide recycling. Here’s what they found:
- Nucleotide salvage pathway enzymes cannot produce triphosphates from epigenetically-modified nucleosides, therefore, the epigenetically-modified ones do not enter the nucleotide pool.
- Cancer cell lines overexpressing CDA died when they were treated with 5hmdC and 5fdC.
- CDA converts 5hmdC and 5fdC into their toxic counterparts 5hmdU (5-hydroxymethyldeoxyuridine) and 5fdU (5-formhyldeoxyuridine), which, when incorporated into DNA in the form of their respective triphosphates, can induce DNA damage and cell death.
- This process can be exploited to kill cancer cells. In two cancer xenograft mouse models, the injection of 5hmdC or 5fdC led to tumor shrinkage and DNA damage.
Melania Zauri the main author of the study says “some cancer cells, i.e. those overexpressing CDA (such as pancreatic cancer), can be targeted therapeutically by exploiting their nucleotide salvaging activity. More studies of efficacy and safety will be needed, but this study offers a clear example of how the study of basic pathways can lead to clinically relevant answers.”
Check out the full details in Nature, July 2015.