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The collaboration of researchers with the participation of specialists from the HSE International Bioinformatics Laboratory has presented a new way to combat intractable melanoma. Scientists have discovered that one of the forms of the DNA molecule, getting into cancer cells, can cause an immune response similar to the body's reaction to the virus. As a result, the cells that support the growth of the tumor die, and the patient begins to respond to anti-cancer therapy again.
Scientists from Russia, the USA, China, Australia and Japan have presented a new way to fight cancer, which is difficult to treat, in particular, does not respond to immunotherapy. The new method is based on the features of the alternative structure of the DNA molecule — Z-DNA. It is a double helix twisted to the left, unlike the classical and most common form of DNA twisted to the right.
Z-DNA was discovered back in 1979, but its role and functions are still insufficiently studied. For a long time, the scientific community did not attach importance to research in this area. Only in recent years has there been evidence that Z-DNA plays an important role in the immune response in the fight against viruses.
Two proteins, ADAR1 and ZBP1, are involved in the formation of Z-DNA in mammals. They are distinguished by the presence of a special structural component — the Za domain, which binds to Z-DNA. The Za domain was previously discovered by Professor Alan Herbert, a scientific consultant at the HSE International Bioinformatics Laboratory.
Proteins with the Za domain are not produced in healthy cells, they are activated by interferon in the case of an inflammatory process. ADAR1 suppresses the autoimmune response, and ZBP1, on the contrary, activates it and launches a cell death program to kill cells infected with the virus. This fact was demonstrated earlier in the work of Professor Balachandran from the Fox Chase Cancer Center, one of the lead authors of the study. In fact, the game of two proteins, ADAR1 and ZBP1, determines the fate of cancer cells: they will survive or die.
ADAR1 and ZBP1 proteins are also produced in connective tissue cells, fibroblasts, during the development of cancer. These are healthy skin cells that cancer cells force to work for themselves to maintain their growth. Cancer cells rely on ADAR1 to suppress the processes of tumor destruction.
During the study of a new anti-cancer drug from the kuraxin group, researchers discovered an interesting feature of the CBL0137 molecule. It turned out that this substance is able to cause mass formation of Z-DNA and directly trigger the death of a cancer cell by activating the ZBP1 protein, regardless of the work of ADAR1.
The tests were carried out on mice with melanoma. Scientists injected a drug containing the CBL0137 molecule directly into the tumor. This caused an immune response, as a result of which fibroblasts supporting tumor growth died, and cancer cells began to respond to immunotherapy again. At the same time, it does not matter which mutation initially provoked cancer.
"The study is an example of an ideal collaboration between experimental and computer groups. Colleagues from the USA generated big data from high-tech experiments, and we performed bioinformatic analysis on this data. The data mining carried out in our laboratory has significantly reduced the time and costs for the experimental part of the work," comments Maria Poptsova. "As a result of this win—win strategy, all project participants won."
The entire computational part of the work was carried out by researchers at the HSE International Bioinformatics Laboratory under the supervision of Maria Poptsova. The bioinformatic analysis was carried out by Alexander Fedorov, a junior researcher at the laboratory. The creation of an artificial intelligence system based on deep learning algorithms for predicting the location of the desired sections of the genome was carried out by a graduate student, lecturer at the Faculty of Computer Science Nazar Beknazarov.
From the point of view of fundamental science, this work is an important step towards understanding the role of alternative DNA structures, such as Z—DNA, in the human body. Research in this area allows us to find new, sometimes unexpected ways to treat severe diseases that have a genetic nature. Usually, many years pass between the discovery of a drug and its release to the market, but in this case, the drug with CBL0137 has already passed clinical safety studies, which means that very soon it will be possible to use it for patients.
The article was published in the journal Nature
The information is taken from the portal "Scientific Russia" (https://scientificrussia.ru /)
PHOTO: From left to right structures of A-, B- and Z-DNA. The structure of a DNA molecule depends on its environment. In the aquatic environment, including most of the DNA in the cell, B-DNA is the most common structure. The structure of A-DNA predominates in dehydrated samples and is similar to double-stranded RNA and DNA/RNA hybrids. Z-DNA is a rarer structure found in DNA associated with certain proteins. © Richard Wheeler (Zephyris)
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