engleski

Resistance of yeast cells to the anti-cancer drug 5-fluorouracil is leveraged by regulating levels of RNA exosome complex subunits and cofactors

The RNA exosome is a conserved complex that catalyzes 3’→5’ degradation and processing of RNA molecules in the nucleus and cytosol of eukaryotic cells. This complex was shown to be involved in the cellular resistance to the anti-cancer drug 5-fluorouracil (5-FU) in yeast Saccharomyces cerevisiae and human cells. 5-FU is an anti-metabolite that is incorporated into DNA and RNA molecules and interferes with various cellular processes, which is why it is widely used for the treatment of colon and breast cancer. However, the development of resistance to 5-FU can be a major obstacle to 5-FU-based therapies, and the molecular mechanisms underlying such resistance remain poorly understood. In this work, we show that expression of the RNA exosome catalytic subunit Rrp6 is regulated by 5-FU treatment in two evolutionarily distant yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. Furthermore, we found that artificially up- or down-regulating the levels of RNA exosome complex subunits and cofactors through overexpression or gene deletion influences the resistance of yeast cells to 5-FU. Given the high degree of conservation of the RNA exosome complex and its cofactors, these results might contribute to elucidation of general molecular mechanisms which underlie 5-FU resistance.

5-fluorouracil ; RNA exosome ; yeast ; cancer resistance

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