Synthetically lethal mutations
Molecular biologists have analyzed combinations of mutations that are fatal for cancer cells
RNF Press Service
Russian molecular biologists have summarized data on the possibilities of using three related enzymes ATM, ATR and DNA-PKcs as targets for targeted anti-tumor therapy.
The cover of Trends in Cancer magazine.
Author: Omar Kantidze.
The results of the study, carried out with the support of a grant from the Presidential Research Projects Program of the Russian Academy of Sciences, will help predict which combinations of mutations are fatal for cancer cells. The review is published in Trends in Cancer (Kantidze et al., Synthetically Lethal Interactions of ATM, ATR, and DNA-PKcs).
Synthetically lethal interactions in biology are combinations of disorders in the work of individual genes or molecular processes that are not individually fatal to a cell, but collectively lead to its death. Combinations of mutations that "turn off" several genes can be lethal, as well as the coincidence of mutations in one gene with the suppression of the activity of a protein encoded by another gene. This phenomenon formed the basis of a new approach to anti-cancer therapy. Many tumors differ from normal tissues by mutations in the genes of enzymes (accelerators and suppressors of chemical reactions) involved in various ways of repairing damaged DNA. Such mutations are not fatal for cells: if one way of DNA repair is not available, there are always alternatives. By suppressing the activity of these alternative systems, it is possible to achieve directed death of tumor cells.
In the published review, molecular biologists from the Institute of Gene Biology of the Russian Academy of Sciences analyzed all studied synthetically lethal interactions of three related enzymes: ATM, ATR and DNA-PKcs. They belong to the same family of kinases (enzymes) involved in the cellular response to DNA damage, but they act differently. Activation of ATR leads to a cell cycle stop. This is necessary so that the damaged DNA is not copied, and the cell has enough time to "fix" it. DNA-PKcs participates in the process of connecting the broken ends of the damaged DNA chain directly, and ATM activates a more accurate way of repairing DNA breaks – homologous recombination. In this case, the damaged chain is restored according to the pattern in a similar (homologous) chromosome.
Currently, 11 inhibitor drugs that suppress the activity of these kinases are at various stages of clinical trials. All of them in the future can become the basis for new, more personalized and accurate methods of cancer treatment. In order to put such methods into practice, it is necessary to know, in combination with which factors disturbances in ATM, ATR and DNA-PKcs are fatal to cells.
The researchers summarized all known lethal interactions of ATM, ATR and DNA-PKcs among themselves and with disorders in the work of other genes. The list turned out to be impressive. For example, it has been proven that simultaneous shutdown of ATM and DNA-PKcs leads to cell death. In this case, both ways of repairing double-stranded DNA breaks are inaccessible to the cell. If the shutdown of any of these kinases coincides with a deficiency of the BRCA1 protein, which is necessary for other ways to restore DNA integrity, the cell also dies. The same thing happens if a cell with inactivating mutations in the ATM or DNA-PKcs genes is affected by DNA-damaging chemical compounds.
Synthetically lethal interactions of ATR kinase are even more diverse. ATR suppression is fatal for cells with non-functioning ATM, with impaired functioning of enzymes involved in DNA reading and synthesis, as well as with an increase in the number of errors in DNA synthesis, the so-called replicative stress. It can be caused by various agents, including substances used in chemotherapy.
"The analysis will make it possible to predict new, as yet unknown synthetically lethal interactions of these three kinases. We can also predict possible mechanisms for tumor cells to acquire resistance to therapy using their inhibitors. Our analysis will help determine for which tumors therapy based on the principle of synthetic lethality is applicable," explains Omar Kantidze, one of the authors of the work, head of the Genome Stability Laboratory at the Institute of Gene Biology of the Russian Academy of Sciences, a grant recipient of the Russian Academy of Sciences. – In our laboratory, we study the mechanisms of synthetic lethality of these kinases and a whole range of factors involved in the cellular response to DNA damage. One of the directions is the synthetically lethal interaction of ATR inhibitors and moderate heat stress. We are trying to understand which DNA repair factors stop working under heat stress and why their inactivation in combination with ATR inhibitors leads to cell death."
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