Academic journal article Genetics

Ribosome Deficiency Protects against ER Stress in Saccharomyces Cerevisiae

Academic journal article Genetics

Ribosome Deficiency Protects against ER Stress in Saccharomyces Cerevisiae

Article excerpt

ABSTRACT In Saccharomyces cerevisiae, 59 of the 78 ribosomal proteins are encoded by duplicated genes that, in most cases, encode identical or very similar protein products. However, different sets of ribosomal protein genes have been identified in screens for various phenotypes, including life span, budding pattern, and drug sensitivities. Due to potential suppressors of growth rate defects among this set of strains in the ORF deletion collection, we regenerated the entire set of haploid ribosomal protein gene deletion strains in a clean genetic background. The new strains were used to create double deletions lacking both paralogs, allowing us to define a set of 14 nonessential ribosomal proteins. Replicative life-span analysis of new strains corresponding to ORF deletion collection strains that likely carried suppressors of growth defects identified 11 new yeast replicative aging genes. Treatment of the collection of ribosomal protein gene deletion strains with tunicamycin revealed a significant correlation between slow growth and resistance to ER stress that was recapitulated by reducing translation of wild-type yeast with cycloheximide. Interestingly, enhanced tunicamycin resistance in ribosomal protein gene deletion mutants was independent of the unfolded protein response transcription factor Hac1. These data support a model in which reduced translation is protective against ER stress by a mechanism distinct from the canonical ER stress response pathway and further add to the diverse yet specific phenotypes associated with ribosomal protein gene deletions.

THE yeast ribosome consists of two subunits, the 40S (small) and 60S (large), which together contain four discrete rRNA species and 78 ribosomal proteins (RPs). In Saccharomyces cerevisiae, 59 of the 78 ribosomal proteins are encoded by a pair of paralogous genes, most of which arose through a genome-wide duplication event roughly 100 million years ago (Wolfe and Shields 1997). Only 12% of the duplicated genome remains, and of the paralogous gene pairs present, a majority of ribosomal proteins genes (RPGs) are in a class that exhibits little or even decelerated evolution (Kellis et al. 2004). Remarkably, 21 of the 59 RPG pairs encode identical proteins, and the others are highly similar (Supporting Information, Table S1). The prevalence of synthetic lethality among RPG paralogs indicates that the two protein products are generally redundant for at least one essential function (Dean et al. 2008).

Despite the significant similarity among RPG paralogs, many reports have described differential effects of deleting only one, and such instances have been observed even in cases where the encoded protein product is identical (Briones et al. 1998). One explanation for this is that the two genes contribute different amounts of protein, and neither is alone sufficient to support wild-type growth. In the case of Rpl16, for example, expression of either RPL16A or RPL16B can rescue the growth defect of cells lacking RPL16B (Rotenberg et al. 1988). Consistently, the RPL16B transcript accumulates to twice the level of the RPL16A transcript, suggesting that under normal conditions, cells lacking RPL16B have a greater deficit in Rpl16 than cells lacking RPL16A. Paralog-specific defects are not uncommon among RPG paralogs and have often been attributed to differences in expression (Abovich and Rosbash 1984; Leer et al. 1984; Herruer et al. 1987; Lucioli et al. 1988; Rotenberg et al. 1988; Briones et al. 1998; Simoff et al. 2009).

More complex relationships between paralogous RPs have also been reported. A study by Komili et al. (2007) showed that transcriptomes from cells in which RPG paralogs had been deleted were considerably different, and mining published data sets for phenotypic effects among cells lacking RPG paralogs also revealed significant differences. Screens for such varied phenotypes as bud site selection (Ni and Snyder 2001), growth of diploid cells haploinsufficient for actin (Haarer et al. …

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