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NSU researchers have predicted variants of a protein that reduces the resistance to chemotherapy of cancer cells
The staff of the Laboratory of Protein Engineering of the Faculty of Natural Sciences of NSU has developed a software pipeline that allows predicting the consequences of mutations for proteins responsible for the resistance of cancer cells to chemotherapy. The results of the work are published in the prestigious international journal Journal of Biological Chemistry (Popov et al., Molecular dynamics approach to identification of new OGG1 cancer-associated somatic variants with impacted activity).
A cancer cell is an ordinary cell of the body, in the DNA of which several mutations occurred at a certain moment, and it began to divide uncontrollably and quickly. Therefore, most chemotherapy drugs are aimed at killing rapidly dividing cells.
– Unfortunately, those perfectly healthy cells that need to divide quickly – stem cells that provide blood renewal, intestinal lining, and hair - also fall under the scope of chemotherapy. Because of this toxicity, it will be much better for the patient if the dosage of the drug is reduced. One of the goals of our work was to find a way to predict mutations in a tumor in which it can be killed with a smaller dosage of medication," says the head of the work, corresponding member of the Russian Academy of Sciences, Doctor of Biological Sciences Dmitry Zharkov.
The effect of many chemotherapy drugs is based on damaging the DNA of a cancer cell as much as possible. But they come into conflict with the DNA repair system. In normal cells, this system protects the genome from mutations and damage. If the DNA of a tumor cell breaks, the repair system does not play on our side: it "corrects" the damage done. It depends on how well the repair system works in a cancer cell, whether it will survive after chemotherapy or not.
The number of mutations in cancer cells reaches many thousands. They also occur in the genes responsible for repair. Sometimes, due to mutations, repair enzymes begin to work worse, and the tumor becomes more vulnerable, and the remaining cells in the patient's body, where there is no such mutation, continue to be resistant. But how to understand which mutation in DNA will weaken repair proteins? To do this, scientists sometimes use special computer programs that analyze how often a certain section of a gene changes in similar proteins. If the site often mutates, it means that it does not carry any special 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, often different analysis algorithms produce completely different results for the same protein, which significantly limits their usefulness.
Researchers from NSU used another predictive method – the method of molecular dynamics. This is a computer simulation that allows you to understand how individual atoms move in the structure of a protein during its operation. This method requires orders of magnitude more computing power than protein sequence analysis, but the modern development of computer technology has allowed it to be used to predict the effect of mutations. Novosibirsk scientists have chosen one of the key enzymes of human DNA repair – 8-oxoguanine-DNA glycosylase. In normal cells, it prevents DNA oxidation, and in cancer cells, it reduces the effectiveness of such commonly used anticancer agents as cisplatin, carmustine and bleomycin. During the study, the staff of the laboratory of protein engineering analyzed the structure of several dozen mutant forms of this protein, which are found in cancerous tumors of various origins. In parallel, the results of computer modeling were tested in an experiment: all the studied mutant variants of the protein were recreated in the laboratory and tested for the ability to correct damaged DNA.
– With the help of our approach, we were able to detect three mutations, each of which completely disables the enzyme. And this is a great success – it means that it has become easier to kill the cell with chemotherapy, and in the presence of such mutations in the tumor, drug concentrations can be reduced. Of course, all this is still experimental data, but this is another step towards personalized medicine, – Dmitry Zharkov believes.
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