Specialized ribosomal protein genes promote drug resistance through modulation of translation

Ribosomes are ubiquitous ribonucleoprotein complexes required for protein synthesis. We show that in budding yeast exposure to drugs alters ribosome composition leading to modification of translation pattern and increased resistance to drug. Exposure to staurosporine repressed translation of cell wall protein genes. Expression of the major paralog of uL30/RPL7 increased cell sensitivity to staurosporine while expression of the minor paralog induced resistance. Remarkably, we found that differences in paralogs function was due to difference in the translation pattern. The minor paralog promoted the translation of cell wall genes with long open reading frames (ORFs), which are normally under-translated in the presence of the major paralog, leading to drug resistance. Reducing the ORF length repressed the minor paralog and staurosporine effects on translation. Together the data reveal a natural mechanism for the optimization of translation through changes in the identity of ribosomal protein genes. Overall design: Total RNA and ribosome associated RNA from wild type cells and cells carrying two copies of either uL30A/RPL7A or uL30B/RPL7B grown in presence or absence of saturosporine was sequenced.