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Abstract
A considerable body of evidence links together mitochondrial dysfunctions, toxic action of metalloid oxyanions, and system and neurodegenerative disorders. In this study we have used the model yeast Saccharomyces cerevisiae to investigate the genetic determinants associated with tellurite resistance/sensitivity. Nitrosoguanidine-induced K2TeO3-resistant mutants were isolated, and one of these mutants, named Sc57-Te5R, was characterized. Both random spore analysis and tetrad analysis and growth of heterozygous (TeS/Te5R) diploid from Sc57-Te5R mutant revealed that nuclear and recessive mutation(s) was responsible for the resistance. To get insight into the mechanisms responsible for K2TeO3-resistance, RNA microarray analyses were performed with K2TeO3-treated and untreated Sc57-Te5R cells. A total of 372 differentially expressed loci were identified corresponding to 6.37% of the S. cerevisiae transcriptome. Of these, 288 transcripts were up-regulated upon K2TeO3 treatment. About half of up-regulated transcripts were associated with the following molecular functions: oxidoreductase activity, structural constituent of cell wall, transporter activity. Comparative whole-genome sequencing allowed us to identify nucleotide variants distinguishing Sc57-Te5R from parental strain Sc57. We detected 15 CDS-inactivating mutations, and found that 3 of them affected genes coding mitochondrial ribosomal proteins (MRPL44 and NAM9) and mitochondrial ribosomal biogenesis (GEP3) pointing out to alteration of mitochondrial ribosome as main determinant of tellurite resistance.
Highlights
We focused on 15 coding sequences (CDS)-inactivating mutations (Table 3) and noticed that 3 of them affect single-copy genes coding mitochondrial ribosomal proteins (MRPL44 and NAM9) or a protein that is involved in mitochondrial ribosomal biogenesis (GEP3)
In this study the model yeast has been used to investigate the molecular mechanisms underlying tellurite resistance/toxicity, a phenotype that has been associated to several neurodegenerative disorders in humans16–18]
We have isolated and characterized at both the genetic and molecular levels an induced mutant of S. cerevisiae yeast, resistant to tellurite by means of nitrosoguanidine treatment
Summary
Tellurite resistance and/or its underlying mechanisms have been directly/indirectly implicated in Friedreich’s ataxia[18], an autosomal recessive neurodegenerative disorder that is caused by mutations affecting frataxin gene (FRDA) coding for a mitochondrial matrix protein[19]. This protein has been implicated in mitochondrial iron homeostasis, its function has not yet been completely elucidated. The biochemical function of tellurite resistance proteins is currently unknown, it is a generally accepted hypothesis that TeR results from conversion of tellurite to a less toxic compound. The identification of mutations conferring tellurite resistance in yeasts should provide insights into cellular functions of fundamental importance to unveil the molecular bases of certain human diseases
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