It has long been known that cancer is characterized by genomic instability. Scientists attributed this to the insufficient activity of the DNA repair system, which monitors the quality of the molecule, finds and removes mutations, and glues breaks together. The bioinformaticians of the Moscow Institute of Physics and Technology and Sechenov University, together with their colleagues, conducted a comprehensive study of this process on the material of tens of thousands of tumor tissue samples and came to a fundamental discovery that radically changes the prevailing opinion. It turned out that almost all the tumors examined differed, on the contrary, in the increased work of the repair systems. The observed strengthening of the repair systems serves primarily the uncontrolled rapid division of cancer cells. But at the same time, the quality control of the resulting DNA is blocked in the tumor: the activity of the most important control mechanism, the so-called G2/M checkpoint, which decides whether to allow the cell to divide or destroy the cell with the damaged genome. The study showed that it is necessary to develop a new class of cancer drugs that will target the release of the G2/M checkpoint, which will give new perspectives in the treatment of most types of tumors. The results of the work were published in the journalDNA repair .
Cancer is a major health problem, causing over 10 million deaths worldwide in 2020. It is expected that by 2040 the number of patients will increase by 47% and reach 28.4 million people. The process of accumulation of mutations, carcinogenesis, is closely related to DNA mutations and loss of control over the integrity of the genome. One of the main molecular mechanisms of cancer development is considered to be DNA repair deficiency, leading to excessive accumulation of genetic changes in the cell. But medical practice has confirmed many times that during treatment, reparation very often intensifies its work and plays on the side of the enemy: on the one hand, it limits the accumulation of mutations in the tumor, and on the other hand, it protects the cancer cell from DNA damage, contributing to the survival of the tumor after radiation therapy. and chemotherapy.
“Thus, we come to a paradox: it is not clear whether DNA repair is friend or foe. Our work for the first time helped answer these questions with the help of a detailed study at the molecular level of the entire complex of repair processes ,” said Anton Buzdin, Professor of the Russian Academy of Sciences, Head of the Laboratory of Translational Genomic Bioinformatics at Moscow Institute of Physics and Technology.
In the course of the study, a team of scientists tested the activation levels of 38 DNA repair pathways for nine of the most common types of human cancer (glioma, breast cancer, colorectal cancer, lung, thyroid, cervical, kidney, stomach and pancreatic cancer). Profiles of several thousand samples from databases were taken for study, as well as about 500 collected experimental tumor samples.
“Having systematized and covered all the processes associated with DNA repair within the framework of a single study, we have shown that, in fact, almost all tumors are characterized by an increased activity of repair mechanisms, even when the genes of the repair system themselves are not affected by any mutations. At the same time, we found that when neoplasms occur, the quality control of the repair work itself is blocked. Normally, our control mechanisms decide if the quality of the DNA in a cell is good, and if not, whether the damaged cell should be left alive or given a chance to repair itself. She is given time to work on the bugs and a strict deadline. If the repair failed to do its job, then the cell cannot divide, and the mechanism of cell death is forcibly triggered in it. It is this quality control mechanism,– added Anton Buzdin.
Scientists propose to reconsider the current understanding of the causes and mechanisms of development of malignant tumors. The main repair mechanisms, as shown by the study, are much more active in tumors than in the norm, although the opposite was previously assumed. Reparation still works and even gives out an increased amount of “repair work”, but without the proper quality. Apparently, the mutations and instability of the genome observed in the tumor are precisely due to a decrease in the work of DNA quality control. Targeting the regulation of molecular DNA repair pathways in tumors can significantly enhance current and future therapeutic approaches for the treatment of cancer.
The study was financially supported by the Russian Science Foundation (grant no. 20–75–10071).