Mutations that affect protein levels impact tumor growth.
Elevated and imbalanced levels of dNTPs — the building blocks of DNA – were found to be associated with the development of colon cancer in a recent study.
The results of the study published in the Proceedings of the National Academy of Sciences could lead to similar discoveries in cancers and other proteins involved in dNTP synthesis.
“Together with other researchers, we have previously shown that small changes in the levels of DNA building blocks increase the mutation rates in yeast cells,” said researcher Andrei Chabes. “This is what got us interested in studying the proteins involved in the regulation of dNTP in cancerous cells. Our objective was to identify mutations that affect dNTP levels and thus increase the mutation rate in cancer cells.”
During the study, researchers found that the protein involved in the breakdown of dNTP, called SAMHD1, was frequently mutated in colon cancer cells.
“What's so remarkable about our observation is that even if only one of the two SAMHD1 gene copies is lost, it affects dNTP levels with an increased mutation rate as a result,” Chabes said. “Together with a deficiency in the protein MLH1, which is involved in the correction of mutations and is often mutated in colon cancers, we can see a huge increase in the number of emerging mutations."
Using mice, yeast, and human cell cultures, researchers were able to demonstrate that cancer-specific mutations eliminated the SAMHD1 function, leading to jumbled levels of dNTP — increasing the mutation rate.
“SAMHD1 is only 1 of several dozen proteins involved in the regulation of dNTPs,” Chabes said. “In theory, a change in function in any of these proteins can affect dNTP levels. We are merely showing the principle. It now remains to be seen how changes in dNTP levels affect the development of colon cancer and if changes in dNTP levels occur in other cancers.”