Identification of an overexpressed yeast gene which prevents aminoglycoside toxicity

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Abstract
Summary: Aminoglycoside antibiotics, used to treat bacterial infections by interfering with proofreading during protein synthesis, cause sensorineural hearing loss in genetically susceptible individuals. The only aminoglycoside-hypersensitivity mutations which have been described in humans are in the mitochondrial 12S rRNA gene, potentially allowing increased antibiotic binding to mitochondrial ribosomes. To identify additional predisposing mutations, a yeast model system was used to isolate genes which interact with or bypass the effects of aminoglycoside antibiotics. A novel yeast gene was isolated which, in high copy, confers neomycin resistance to yeast transformants. The neomycin-resistance 1 gene (NEO1) encodes a potential 1151 aa integral membrane protein, most homologous to the yeast DRS2 gene product, a Ca2+-ATPase involved in cytoplasmic ribosome assembly. The N-terminus of Neo1p is partially homologous to abrin A-chain, another protein which interacts with cytoplasmic ribosomes. Mutagenesis experiments demonstrate that the NEO1 product is essential for vegetative growth and that the drug-resistance phenotype requires ATPase function.

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