Scientists at NSU’s Natural Sciences Department Protein Engineering Laboratory developed a software pipeline that predicts the effects of mutations on proteins responsible for cancer cell resistance to chemotherapy. Their results are published in the prestigious international “Journal of Biological Chemistry”.
A cancer cell is an ordinary cell where several mutations of DNA occurred causing it to divide uncontrollably and quickly. Therefore, most chemotherapy drugs are targeted at killing rapidly dividing cells.
Dmitry Zharkov, Head of the research team, Corresponding Member of the Russian Academy of Sciences and Doctor of Biological Sciences, talked about their work,
Unfortunately, chemotherapy also targets perfectly healthy cells that divide quickly such as stem cells that provide blood renewal, intestinal lining, and hair. Because of this toxicity, a reduced drug dosage is much better for the patient. One of the goals of our work was to find a way to predict mutations in a tumor so it can be killed with a lower dosage of the drug,
Many chemotherapy drugs work to damage the DNA of the cancer cell as much as possible. However, they come into conflict with the DNA repair system. In normal cells, this system protects the genome fr om mutation and damage. If the DNA of a tumor cell breaks, the repair system “corrects” the damage done. How well the repair system works in a cancer cell determines whether it survives chemotherapy or not.
There are thousands of cancer cell mutations. They also occur in the genes responsible for repair. Sometimes, due to mutations, the repair enzymes do not work as well and the tumor becomes more vulnerable, while the rest of the cells in the patient's body, wh ere there is no such mutation, continue to be resistant. How can we understand which mutation in DNA will weaken the repair proteins? Sometimes scientists use special computer programs to analyze how often a certain section of a gene changes in similar proteins. If a site frequently mutates, it means that it is not of any particular importance for the functionality of the protein. If it does not change, the program concludes that it is so important for the protein that any mutation in it weakens or kills the cell. However, different analytical algorithms often produce completely different results for the same protein and that significantly limits their usefulness.
The NSU researchers used another method for prediction, the molecular dynamics method. This is a computer simulation that allows you to understand how individual atoms in the structure of a protein move when it works. This method requires orders of magnitude more computing power than protein sequence analysis, but modern developments in computer technology has made it possible to use it to predict the effect of mutations. The scientists chose one of the key human DNA repair enzymes, 8-oxoguanine DNA glycosylase. In normal cells, it prevents DNA oxidation and in cancer cells it reduces the effectiveness of commonly used anticancer agents such as cisplatin, carmustine, and bleomycin. In the course of the Protein Engineering Laboratory study, they analyzed the structure of several dozen mutant forms of this protein that are found in cancerous tumors of various origins. In parallel, the results of computer modeling were verified experimentally with all mutant variants of the protein being examined recreated under laboratory conditions and tested for their ability to repair damaged DNA.
With our approach, we were able to find three mutations, each of which completely disables the enzyme. This is a great success, it means that it is easier to kill the cell with chemotherapy and in the presence of such mutations in the tumor, the concentration of drugs can be reduced. Of course, all this is still experimental data, but it is another step towards personalized medicine.