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Duplicated ribosomal protein paralogs promote alternative translation and drug resistance.

ABSTRACT: Ribosomes are often seen as monolithic machines produced from uniformly regulated genes. However, in yeast most ribosomal proteins come from duplicated genes. Here, we demonstrate that gene duplication may serve as a stress-adaptation mechanism modulating the global proteome through the differential expression of ribosomal protein paralogs. Our data indicate that the yeast paralog pair of the ribosomal protein L7/uL30 produces two differentially acetylated proteins. Under normal conditions most ribosomes incorporate the hypo-acetylated major form favoring the translation of genes with short open reading frames. Exposure to drugs, on the other hand, increases the production of ribosomes carrying the hyper-acetylated minor paralog that increases translation of long open reading frames. Many of these paralog-dependent genes encode cell wall proteins that could promote tolerance to drugs as their translation increases after exposure to drugs. Together our data suggest a mechanism of translation control that functions through a differential use of near-identical ribosomal protein isoforms.

SUBMITTER: Malik Ghulam M

PROVIDER: S-EPMC9399092 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Duplicated ribosomal protein paralogs promote alternative translation and drug resistance.

Malik Ghulam Mustafa M Catala Mathieu M Reulet Gaspard G Scott Michelle S MS Abou Elela Sherif S

Nature communications 20220823 1

Ribosomes are often seen as monolithic machines produced from uniformly regulated genes. However, in yeast most ribosomal proteins come from duplicated genes. Here, we demonstrate that gene duplication may serve as a stress-adaptation mechanism modulating the global proteome through the differential expression of ribosomal protein paralogs. Our data indicate that the yeast paralog pair of the ribosomal protein L7/uL30 produces two differentially acetylated proteins. Under normal conditions most ...[more]

PMID: 35999447

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Project description:Cohesin is a protein complex known for its essential role in chromosome segregation. However, cohesin and associated factors have additional functions in transcription, DNA damage repair, and chromosome condensation. The human cohesinopathy diseases are thought to stem not from defects in chromosome segregation but from gene expression. The role of cohesin in gene expression is not well understood. We used budding yeast strains bearing mutations analogous to the human cohesinopathy disease alleles under control of their native promoter to study gene expression. These mutations do not significantly affect chromosome segregation. Transcriptional profiling reveals that many targets of the transcriptional activator Gcn4 are induced in the eco1-W216G mutant background. The upregulation of Gcn4 was observed in many cohesin mutants, and this observation suggested protein translation was reduced. We demonstrate that the cohesinopathy mutations eco1-W216G and smc1-Q843? are associated with defects in ribosome biogenesis and a reduction in the actively translating fraction of ribosomes, eiF2?-phosphorylation, and (35)S-methionine incorporation, all of which indicate a deficit in protein translation. Metabolic labeling shows that the eco1-W216G and smc1-Q843? mutants produce less ribosomal RNA, which is expected to constrain ribosome biogenesis. Further analysis shows that the production of rRNA from an individual repeat is reduced while copy number remains unchanged. Similar defects in rRNA production and protein translation are observed in a human Roberts syndrome cell line. In addition, cohesion is defective specifically at the rDNA locus in the eco1-W216G mutant, as has been previously reported for Roberts syndrome. Collectively, our data suggest that cohesin proteins normally facilitate production of ribosomal RNA and protein translation, and this is one way they can influence gene expression. Reduced translational capacity could contribute to the human cohesinopathies.

Dataset Information

Duplicated ribosomal protein paralogs promote alternative translation and drug resistance.

Publications

Duplicated ribosomal protein paralogs promote alternative translation and drug resistance.

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