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On the problem of multidrug resistance: hypermutability as a mechanism to defense metabolic targets from toxic xenobiotics
- Institute of Molecular Biology and Genetics, NAS of Ukraine
150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680
Multidrug resistance (mdr), a scourge of modern pharmacology, is studied mainly as related to the function of multidrug exporters and cell overcrowding with proteins. However, often it brings no solution to the problem. Here we briefly summarize achievements in the mdr study and analyze our results showing that mdr may emerge due to simultaneous mutations arisen in different tightly linked genes united into a cassette. The latter may be specially localized inside the cell (we dubbed this as an environsome) so that it faces, unlike other genes, the intracellular space and the main intracellular flux. There are ~100 environsomes per cell, the chemoresistant phenotype may be due to a mutation in one of them. In case of a mutagen involved into the flux the cassette is the first to become an area of effective local mutagenesis and develops many mutations simultaneously. If the cassette codes for natively unfolded proteins and the transition disorder/order due to mutations becomes possible it may change the geometry of intracellular space and cause ligand and target sequestration, leading to the cell multiple chemoresistance).
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