Misregulation of DNA building blocks mapped in colon cancer development.
Deoxyribonucleic acid (DNA) is a molecule that contains the genetic information to develop and maintain life. DNA consists of four bases, namely adenine, cytosine, guanine, and thymine. These four bases convey huge amounts of information and are linked to a sugar, deoxyribose, and a phosphate group to form a nucleotide, the building block of DNA. When cells divide, the proper balance between the four DNA building blocks is required in order for the DNA to be copied without the introduction of potentially harmful mutations. Now, a study from researchers at Umeå University shows a connection between levels of DNA building blocks, also known as dNTPs, and colon cancer. This opensource study is published in the Proceedings of the National Academy of Sciences.
Previous studies show that the concentrations of dNTPs are controlled by several dozen proteins, and mutations or a change in abundance in any of these could in principle result in a distortion of the dNTP pool. SAMHD1 is a dual-function enzyme with both nuclease and deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase) activities. SAMHD1 has been identified as a potential driver gene in chronic lymphatic leukemia, where it is recurrently mutated in early stages of tumour development. However, it is unknown whether SAMHD1 somatic mutations found in cancers affect its dNTPase activity. Earlier studies from the lab and other researchers have shown that small changes in the levels of DNA building blocks increase the mutation rates in yeast cells. Therefore the group hypothesized that the proteins involved in the regulation of dNTP where involved in the proliferation cancerous cells. The current study shows that the inactivation of one SAMHD1 allele is sufficient to elevate dNTP pools and suggests that heterozygous cancer-associated SAMHD1 mutations increase mutation rates in cancer cells.
The current study shows that the protein SAMHD1, which is involved in the break-down of dNTP, is often mutated in colon cancer cells. Results show that in mice, yeast, and cultures of human cells these cancer-specific mutations eliminated the SAMHD1 function which led to an elevation and imbalance of dNTP levels, increasing the mutation rate. Data findings show 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.
The researchers state that together with a deficiency in the protein MLH1, which is involved in the correction of mutations and is often mutated in colon cancers, they can see a huge increase in the number of emerging mutations. They go on to add that they have reason to believe the results will lead to other similar discoveries, both in other cancers and in other proteins involved in dNTP synthesis.
The team surmise that SAMHD1 is only one of several dozen proteins involved in the regulation of dNTPs and in theory, a change in function in any of these proteins can affect dNTP levels. For the future, the researchers state that 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.
Source: Umeå University