Methylation of yeast ribosomal protein Rpl3 promotes translational elongation fidelity

Al-Hadid, Qais; Roy, Kevin; Chanfreau, Guillaume; Clarke, Steven

doi:10.1261/rna.054569.115

Cited by 30 publications

(47 citation statements)

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“…Yeast hpm1 null cells have a pronounced deficiency of 60S subunits reflecting a significant defect in early rRNA processing with the accumulation of 35S and 23S intermediate RNA species (74). Using a dual luciferase reporter system, we have also been able to show significant (>2-fold) misincorporation of amino acids in cells deficient in Hpm1 (75). Hpm1-deficient cells also demonstrated increased resistance to the ribosome-binding antibiotics cycloheximide and verrucarin A, suggesting structural changes in the ribosome that accompanied the abnormal ribosome biogenesis (76).…”

Section: Protein Histidine Methyltransferasesmentioning

confidence: 85%

The ribosome: A hot spot for the identification of new types of protein methyltransferases

Clarke¹

2018

Journal of Biological Chemistry

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Cellular physiology depends on the alteration of protein structures by covalent modification reactions. Using a combination of bioinformatic, genetic, biochemical, and mass spectrometric approaches, it has been possible to probe ribosomal proteins from the yeast Saccharomyces cerevisiae for posttranslationally methylated amino acid residues and for the enzymes that catalyze these modifications. These efforts have resulted in the identification and characterization of the first protein histidine methyltransferase, the first N-terminal protein methyltransferase, two unusual types of protein arginine methyltransferases, and a new type of cysteine methylation. Two of these enzymes may modify their substrates during ribosomal assembly because the final methylated histidine and arginine residues are buried deep within the ribosome with contacts only with RNA. Two of these modifications occur broadly in eukaryotes, including humans, while the others demonstrate a more limited phylogenetic range. Analysis of strains where the methyltransferase genes are deleted has given insight into the physiological roles of these modifications. These reactions described here add diversity to the modifications that generate the typical methylated lysine and arginine residues previously described in histones and other proteins. Regulation of biological function by protein methylation reactionsIt is more and more apparent just how much of biological function is dependent upon posttranslational modifications (1). The human genome encodes some 900 enzymes catalyzing just protein phosphorylation or ubiquitination (2,3). However, it is now clear that methyl groups can stand beside phosphate groups and ubiquitin as major players in controlling the physiological functions of proteins. We are beginning to understand how the much greater diversity of protein methylation reactions can give rise to a greater diversity of function (1,4-8). We are also learning the importance of crosstalk between protein and DNA methylation reactions (9) and among protein methylation, phosphorylation, acetylation, and ubiquitination reactions (10-12). Finally, we are discovering how alterations in protein methylation pathways can lead to human pathology, particularly in cancer (13-15).The collection of over sixty human protein arginine and lysine methyltransferases that leave histone "marks" recognized by reader proteins to guide gene expression are perhaps the poster children for the importance of protein methyltransferases (16-17). However, recent work has emphasized the importance of methylating non-histone substrates at these residues, particularly ribosomal proteins, translation factors, and transcription factors in a wide variety of organisms (7,8,15,18,19). Furthermore, the methylation of lysine and arginine residues represents just the tip of the iceberg in protein methylation -modifications have also been established at histidine, modified histidine (diphthamide), glutamate, glutamine, asparagine, Lisoaspartate, D-aspartate, cysteine, isoprenylcysteine, me...

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Section: Protein Histidine Methyltransferasesmentioning

confidence: 85%

The ribosome: A hot spot for the identification of new types of protein methyltransferases

Clarke¹

2018

Journal of Biological Chemistry

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“…A total of four independent profiles were obtained for wild type cells, five profiles for hpm1 Δ cells, and two profiles for each of the other strains. The profiles for wild type and hpm1 Δ cells were previously reported [13]. A representative profile for each strain is shown here.…”

Section: Figmentioning

confidence: 99%

“…Wild type was assayed 11 independent times, hpm1 Δ 8 times and mutants were assayed three independent times. Data for the wild type and hpm1 Δ cells were previously reported [13]. (B) Same as in (A) except a UAG stop codon was used.…”

Section: Figmentioning

confidence: 99%

“…We previously showed that the yeast methyltransferase, Hpm1, plays an important role in ribosome biogenesis and translation [12,13]. Cells deficient in Hpm1 exhibited defects in 60S large ribosomal subunit synthesis and decreased translation elongation fidelity [12,13].…”

Section: Introductionmentioning

confidence: 99%

“…Cells deficient in Hpm1 exhibited defects in 60S large ribosomal subunit synthesis and decreased translation elongation fidelity [12,13]. To determine if the nine other known ribosomal protein methyltransferases in S. cerevisiae are playing similar roles as Hpm1, we investigated the consequences of depleting each ribosomal protein methyltransferase on ribosome biogenesis and translation.…”

Section: Introductionmentioning

confidence: 99%

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Ribosomal protein methyltransferases in the yeast Saccharomyces cerevisiae : Roles in ribosome biogenesis and translation

Al-Hadid

White

Clarke

2016

Biochemical and Biophysical Research Communications

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A significant percentage of the methyltransferasome in Saccharomyces cerevisiae and higher eukaryotes is devoted to methylation of the translational machinery. Methylation of the RNA components of the translational machinery has been studied extensively and is important for structure stability, ribosome biogenesis, and translational fidelity. However, the functional effects of ribosomal protein methylation by their cognate methyltransferases are still largely unknown. Previous work has shown that the ribosomal protein Rpl3 methyltransferase, histidine protein methyltransferase 1 (Hpm1), is important for ribosome biogenesis and translation elongation fidelity. In this study, yeast strains deficient in each of the ten ribosomal protein methyltransferases in S. cerevisiae were examined for potential defects in ribosome biogenesis and translation. Like Hpm1-deficient cells, loss of four of the nine other ribosomal protein methyltransferases resulted in defects in ribosomal subunit synthesis. All of the mutant strains exhibited resistance to the ribosome inhibitors anisomycin and/or cycloheximide in plate assays, but not in liquid culture. Translational fidelity assays measuring stop codon readthrough, amino acid misincorporation, and programmed −1 ribosomal frameshifting, revealed that eight of the ten enzymes are important for translation elongation fidelity and the remaining two are necessary for translation termination efficiency. Altogether, these results demonstrate that ribosomal protein methyltransferases in S. cerevisiae play important roles in ribosome biogenesis and translation.

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Ribosome heterogeneity and specialization in development

2021

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Regulation of protein synthesis is a vital step in controlling gene expression, especially during development. Over the last 10 years, it has become clear that rather than being homogeneous machines responsible for mRNA translation, ribosomes are highly heterogeneous and can play an active part in translational regulation. These “specialized ribosomes” comprise of specific protein and/or rRNA components, which are required for the translation of particular mRNAs. However, while there is extensive evidence for ribosome heterogeneity, support for specialized functions is limited. Recent work in a variety of developmental model organisms has shed some light on the biological relevance of ribosome heterogeneity. Tissue‐specific expression of ribosomal components along with phenotypic analysis of ribosomal gene mutations indicate that ribosome heterogeneity and potentially specialization are common in key development processes like embryogenesis, spermatogenesis, oogenesis, body patterning, and neurogenesis. Several examples of ribosome specialization have now been proposed but strong links between ribosome heterogeneity, translation of specific mRNAs by defined mechanisms, and role of these translation events remain elusive. Furthermore, several studies have indicated that heterogeneous ribosome populations are a product of tissue‐specific expression rather than specialized function and that ribosomal protein phenotypes are the result of extra‐ribosomal function or overall reduced ribosome levels. Many important questions still need to be addressed in order to determine the functional importance of ribosome heterogeneity to development and disease, which is likely to vary across systems. It will be essential to dissect these issues to fully understand diseases caused by disruptions to ribosomal composition, such as ribosomopathies. This article is categorized under: Translation > Translation Regulation Translation > Ribosome Structure/Function RNA in Disease and Development > RNA in Development

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Methylation of yeast ribosomal protein Rpl3 promotes translational elongation fidelity

Cited by 30 publications

References 51 publications

The ribosome: A hot spot for the identification of new types of protein methyltransferases

The ribosome: A hot spot for the identification of new types of protein methyltransferases

Ribosomal protein methyltransferases in the yeast Saccharomyces cerevisiae : Roles in ribosome biogenesis and translation

Ribosome heterogeneity and specialization in development

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