The roles of ribosomal proteins in nasopharyngeal cancer: culprits, sentinels or both

AbstractRibosomal protein genes encode products that are essential for cellular protein biosynthesis and are major components of ribosomes. Canonically, they are involved in the complex system of ribosome biogenesis pivotal to the catalysis of protein translation. Amid this tightly organised process, some ribosomal proteins have unique spatial and temporal physiological activity giving rise to their extra-ribosomal functions. Many of these extra-ribosomal roles pertain to cellular growth and differentiation, thus implicating the involvement of some ribosomal proteins in organogenesis. Consequently, dysregulated functions of these ribosomal proteins could be linked to oncogenesis or neoplastic transformation of human cells. Their suspected roles in carcinogenesis have been reported but not specifically explained for malignancy of the nasopharynx. This is despite the fact that literature since one and half decade ago have documented the association of ribosomal proteins to nasopharyngeal cancer. In this review, we explain the association and contribution of dysregulated expression among a subset of ribosomal proteins to nasopharyngeal oncogenesis. The relationship of these ribosomal proteins with the cancer are explained. We provide information to indicate that the dysfunctional extra-ribosomal activities of specific ribosomal proteins are tightly involved with the molecular pathogenesis of nasopharyngeal cancer albeit mechanisms yet to be precisely defined. The complete knowledge of this will impact future applications in the effective management of nasopharyngeal cancer.

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Control of ribosomal protein synthesis by the Microprocessor complex

Science Signaling ◽

10.1126/scisignal.abd2639 ◽

2021 ◽

Vol 14 (671) ◽

pp. eabd2639

Author(s):

Xuan Jiang ◽

Amit Prabhakar ◽

Stephanie M. Van der Voorn ◽

Prajakta Ghatpande ◽

Barbara Celona ◽

...

Keyword(s):

Protein Synthesis ◽

Ribosomal Protein ◽

Nuclear Export ◽

Ribosomal Proteins ◽

Ribosome Biogenesis ◽

Cellular Growth ◽

Ribosomal Protein Genes ◽

Erythroid Progenitors ◽

Microprocessor Complex ◽

Ribosomal Protein Synthesis

Ribosome biogenesis in eukaryotes requires the coordinated production and assembly of 80 ribosomal proteins and four ribosomal RNAs (rRNAs), and its rate must be synchronized with cellular growth. Here, we showed that the Microprocessor complex, which mediates the first step of microRNA processing, potentiated the transcription of ribosomal protein genes by eliminating DNA/RNA hybrids known as R-loops. Nutrient deprivation triggered the nuclear export of Drosha, a key component of the Microprocessor complex, and its subsequent degradation by the E3 ubiquitin ligase Nedd4, thereby reducing ribosomal protein production and protein synthesis. In mouse erythroid progenitors, conditional deletion of Drosha led to the reduced production of ribosomal proteins, translational inhibition of the mRNA encoding the erythroid transcription factor Gata1, and impaired erythropoiesis. This phenotype mirrored the clinical presentation of human “ribosomopathies.” Thus, the Microprocessor complex plays a pivotal role in synchronizing protein synthesis capacity with cellular growth rate and is a potential drug target for anemias caused by ribosomal insufficiency.

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Control of ribosomal protein synthesis by Microprocessor complex

10.1101/2020.04.24.060236 ◽

2020 ◽

Author(s):

Xuan Jiang ◽

Amit Prabhakar ◽

Stephanie M. Van der Voorn ◽

Prajakta Ghatpande ◽

Barbara Celona ◽

...

Keyword(s):

Cell Growth ◽

Nuclear Export ◽

Ribosomal Proteins ◽

Ribosome Biogenesis ◽

Cellular Growth ◽

New Paradigm ◽

Erythroid Progenitors ◽

Conditional Deletion ◽

Microprocessor Complex ◽

Ribosomal Protein Synthesis

AbstractRibosome biogenesis in eukaryotes requires stoichiometric production and assembly of 80 ribosomal proteins (RPs) and 4 ribosomal RNAs, and its rate must be coordinated with cellular growth. The indispensable regulator of RP biosynthesis is the 5’-terminal oligopyrimidine (TOP) motif, spanning the transcription start site of all RP genes. Here we show that the Microprocessor complex, previously linked to the first step of processing microRNAs (miRNAs), coregulates RP expression by binding the TOP motif of nascent RP mRNAs and stimulating transcription elongation via resolution of DNA/RNA hybrids. Cell growth arrest triggers nuclear export and degradation of the Microprocessor protein Drosha by the E3 ubiquitin ligase Nedd4, accumulation of DNA/RNA hybrids at RP gene loci, decreased RP synthesis, and ribosome deficiency, hence synchronizing ribosome production with cell growth. Conditional deletion of Drosha in erythroid progenitors phenocopies human ribosomopathies, in which ribosomal insufficiency leads to anemia. Outlining a miRNA-independent role of the Microprocessor complex at the interphase between cell growth and ribosome biogenesis offers a new paradigm by which cells alter their protein biosynthetic capacity and cellular metabolism.

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Genome-Wide Identification, Evolution and Expression of the Complete Set of Cytoplasmic Ribosomal Protein Genes in Nile Tilapia

International Journal of Molecular Sciences ◽

10.3390/ijms21041230 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1230

Author(s):

Gangqiao Kuang ◽

Wenjing Tao ◽

Shuqing Zheng ◽

Xiaoshuang Wang ◽

Deshou Wang

Keyword(s):

Ribosomal Proteins ◽

Nile Tilapia ◽

Ribosome Biogenesis ◽

Developmental Stages ◽

Expression Profiles ◽

Ribosomal Protein Genes ◽

Expression Levels ◽

Sexually Dimorphic Expression ◽

Complete Set ◽

Almost All

Ribosomal proteins (RPs) are indispensable in ribosome biogenesis and protein synthesis, and play a crucial role in diverse developmental processes. In the present study, we carried out a comprehensive analysis of RPs in chordates and examined the expression profiles of the complete set of 92 cytoplasmic RP genes in Nile tilapia. The RP genes were randomly distributed throughout the tilapia genome. Phylogenetic and syntenic analyses revealed the existence of duplicated RP genes from 2R (RPL3, RPL7, RPL22 and RPS27) and 3R (RPL5, RPL19, RPL22, RPL41, RPLP2, RPS17, RPS19 and RPS27) in tilapia and even more from 4R in common carp and Atlantic salmon. The RP genes were found to be expressed in all tissues examined, but their expression levels differed among different tissues. Gonadal transcriptome analysis revealed that almost all RP genes were highly expressed, and their expression levels were highly variable between ovaries and testes at different developmental stages in tilapia. No sex- and stage-specific RP genes were found. Eleven RP genes displayed sexually dimorphic expression with nine higher in XY gonad and two higher in XX gonad at all stages examined, which were proved to be phenotypic sex dependent. Quantitative real-time PCR and immunohistochemistry ofRPL5b and RPL24 were performed to validate the transcriptome data. The genomic resources and expression data obtained in this study will contribute to a better understanding of RPs evolution and functions in chordates.

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A ribosome-anchored chaperone network that facilitates eukaryotic ribosome biogenesis

The Journal of Cell Biology ◽

10.1083/jcb.201001054 ◽

2010 ◽

Vol 189 (1) ◽

pp. 69-81 ◽

Cited By ~ 66

Author(s):

Véronique Albanèse ◽

Stefanie Reissmann ◽

Judith Frydman

Keyword(s):

Protein Folding ◽

Ribosome Biogenesis ◽

De Novo ◽

Protein Biosynthesis ◽

Critical Role ◽

Cellular Protein ◽

Complex Process ◽

J Proteins ◽

Oligomeric Complex ◽

Chaperone Network

Molecular chaperones assist cellular protein folding as well as oligomeric complex assembly. In eukaryotic cells, several chaperones termed chaperones linked to protein synthesis (CLIPS) are transcriptionally and physically linked to ribosomes and are implicated in protein biosynthesis. In this study, we show that a CLIPS network comprising two ribosome-anchored J-proteins, Jjj1 and Zuo1, function together with their partner Hsp70 proteins to mediate the biogenesis of ribosomes themselves. Jjj1 and Zuo1 have overlapping but distinct functions in this complex process involving the coordinated assembly and remodeling of dozens of proteins on the ribosomal RNA (rRNA). Both Jjj1 and Zuo1 associate with nuclear 60S ribosomal biogenesis intermediates and play an important role in nuclear rRNA processing, leading to mature 25S rRNA. In addition, Zuo1, acting together with its Hsp70 partner, SSB (stress 70 B), also participates in maturation of the 35S rRNA. Our results demonstrate that, in addition to their known cytoplasmic roles in de novo protein folding, some ribosome-anchored CLIPS chaperones play a critical role in nuclear steps of ribosome biogenesis.

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The High-resolution Timeline of Expression of Ribosomal Protein Genes in Yeast

10.1101/170399 ◽

2017 ◽

Author(s):

Xueling Li ◽

Gang Chen ◽

Bernard Fongang ◽

Dirar Homouz ◽

Maga Rowicka ◽

...

Keyword(s):

Gene Expression ◽

High Resolution ◽

Ribosomal Proteins ◽

Ribosome Biogenesis ◽

Center Of Mass ◽

Regulatory Elements ◽

Ribosomal Protein Genes ◽

Translational Initiation ◽

Expression Of Genes ◽

Expression Time

AbstractThe yeast ribosome is a complex molecular machine built from four rRNAs and over 70 r-proteins. Ribosome biogenesis involves ordered incorporation of ribosomal proteins, accompanied by and association and dissociation of other proteins specific to different stages of the process. By model-based analysis of temporal profiles of gene expression in a metabolically regulated system, we obtained an accurate, high-resolution estimation of the time of expression of genes coding for proteins involved in ribosome biogenesis. The ribosomal proteins are expressed in a sequence that spans approximately 25-minutes under metabolically regulated conditions. The genes coding for proteins incorporated into the mature ribosome are expressed significantly later than those that are not incorporated, but are otherwise involved in ribosome biogenesis, localization and assembly, rRNA processing and translational initiation. The relative expression time of proteins localized within specified neighborhood is significantly correlated with the distance to the centroid of the mature ribosome: protein localized closer to the center of mass of the entire complex tend to be expressed earlier than the protein localized further from the center. The timeline of gene expression also agrees with the known dependencies between recruitment of specific proteins into the mature ribosome. These findings are consistent in two independent experiments. We have further identified regulatory elements correlated with the time of regulation, including a possible dependence of expression time on the position of the RAP1 binding site within the 5’UTR.

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Parallel Concerted Evolution of Ribosomal Protein Genes in Fungi and Its Adaptive Significance

10.1101/751792 ◽

2019 ◽

Author(s):

Alison Mullis ◽

Zhaolian Lu ◽

Yu Zhan ◽

Tzi-Yuan Wang ◽

Judith Rodriguez ◽

...

Keyword(s):

Concerted Evolution ◽

Ribosomal Proteins ◽

Ribosome Biogenesis ◽

Gene Dosage ◽

High Growth ◽

Fungal Species ◽

Physiological Data ◽

Ribosomal Protein Genes ◽

Cellular Machinery ◽

Dosage Balance

ABSTRACTRibosomal proteins (RPs) genes encode structure components of ribosomes, the cellular machinery for protein synthesis. A single functional copy has been maintained in most of 78-80 RP families in animals due to evolutionary constraints imposed by gene dosage balance. Some fungal species have maintained duplicate copies in most RP families. How the RP genes were duplicated and maintained in these fungal species, and their functional significance remains unresolved. To address these questions, we identified all RP genes from 295 fungi and inferred the timing and nature of gene duplication for all RP families. We found that massive duplications of RP genes have independently occurred by different mechanisms in three distantly related lineages. The RP duplicates in two of them, budding yeast and Mucoromycota, were mainly created by whole genome duplication (WGD) events. However, in fission yeasts, duplicate RP genes were likely generated by retroposition, which is unexpected considering their dosage sensitivity. The sequences of most RP paralogs in each species have been homogenized by repeated gene conversion, demonstrating parallel concerted evolution, which might have facilitated the retention of their duplicates. Transcriptomic data suggest that the duplication and retention of RP genes increased RP transcription abundance. Physiological data indicate that increased ribosome biogenesis allowed these organisms to rapidly consuming sugars through fermentation while maintaining high growth rates, providing selective advantages to these species in sugar-rich environments.

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A memory of eS25 loss drives resistance phenotypes

Nucleic Acids Research ◽

10.1093/nar/gkaa444 ◽

2020 ◽

Author(s):

Alex G Johnson ◽

Ryan A Flynn ◽

Christopher P Lapointe ◽

Yaw Shin Ooi ◽

Michael L Zhao ◽

...

Keyword(s):

Ribosomal Protein ◽

Translational Control ◽

Ribosomal Proteins ◽

Ribosomal Protein Gene ◽

Human Cell Line ◽

Cellular Protein ◽

Ribosomal Protein Genes ◽

Genomic Locus ◽

Cellular Phenotypes

Abstract In order to maintain cellular protein homeostasis, ribosomes are safeguarded against dysregulation by myriad processes. Remarkably, many cell types can withstand genetic lesions of certain ribosomal protein genes, some of which are linked to diverse cellular phenotypes and human disease. Yet the direct and indirect consequences from these lesions are poorly understood. To address this knowledge gap, we studied in vitro and cellular consequences that follow genetic knockout of the ribosomal proteins RPS25 or RACK1 in a human cell line, as both proteins are implicated in direct translational control. Prompted by the unexpected detection of an off-target ribosome alteration in the RPS25 knockout, we closely interrogated cellular phenotypes. We found that multiple RPS25 knockout clones display viral- and toxin-resistance phenotypes that cannot be rescued by functional cDNA expression, suggesting that RPS25 loss elicits a cell state transition. We characterized this state and found that it underlies pleiotropic phenotypes and has a common rewiring of gene expression. Rescuing RPS25 expression by genomic locus repair failed to correct for the phenotypic and expression hysteresis. Our findings illustrate how the elasticity of cells to a ribosome perturbation can drive specific phenotypic outcomes that are indirectly linked to translation and suggests caution in the interpretation of ribosomal protein gene mutation data.

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The Impact of the Stringent Response on TRAFAC GTPases and Prokaryotic Ribosome Assembly

Cells ◽

10.3390/cells8111313 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1313 ◽

Cited By ~ 11

Author(s):

Bennison ◽

Irving ◽

Corrigan

Keyword(s):

Ribosomal Proteins ◽

Cellular Response ◽

Ribosome Biogenesis ◽

Stringent Response ◽

Protein Translation ◽

Bound State ◽

Ribosome Assembly ◽

Rrna Transcription ◽

Stress Sensing ◽

The Impact

Many facets of ribosome biogenesis and function, including ribosomal RNA (rRNA) transcription, 70S assembly and protein translation, are negatively impacted upon induction of a nutrient stress-sensing signalling pathway termed the stringent response. This stress response is mediated by the alarmones guanosine tetra- and penta-phosphate ((p)ppGpp), the accumulation of which leads to a massive cellular response that slows growth and aids survival. The 70S bacterial ribosome is an intricate structure, with assembly both complex and highly modular. Presiding over the assembly process is a group of P-loop GTPases within the TRAFAC (Translation Factor Association) superclass that are crucial for correct positioning of both early and late stage ribosomal proteins (r-proteins) onto the rRNA. Often described as ‘molecular switches’, members of this GTPase superfamily readily bind and hydrolyse GTP to GDP in a cyclic manner that alters the propensity of the GTPase to carry out a function. TRAFAC GTPases are considered to act as checkpoints to ribosome assembly, involved in binding to immature sections in the GTP-bound state, preventing further r-protein association until maturation is complete. Here we review our current understanding of the impact of the stringent response and (p)ppGpp production on ribosome maturation in prokaryotic cells, focusing on the inhibition of (p)ppGpp on GTPase-mediated subunit assembly, but also touching upon the inhibition of rRNA transcription and protein translation.

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NSR1 is required for pre-rRNA processing and for the proper maintenance of steady-state levels of ribosomal subunits

Molecular and Cellular Biology ◽

10.1128/mcb.12.9.3865-3871.1992 ◽

1992 ◽

Vol 12 (9) ◽

pp. 3865-3871

Author(s):

W C Lee ◽

D Zabetakis ◽

T Mélèse

Keyword(s):

Nuclear Localization ◽

Ribosomal Proteins ◽

Ribosome Biogenesis ◽

Protein Translation ◽

Striking Similarity ◽

Growth Defect ◽

Nuclear Localization Sequence ◽

Rrna Processing ◽

Ribosomal Subunits ◽

Localization Sequence

NSR1 is a yeast nuclear localization sequence-binding protein showing striking similarity in its domain structure to nucleolin. Cells lacking NSR1 are viable but have a severe growth defect. We show here that NSR1, like nucleolin, is involved in ribosome biogenesis. The nsr1 mutant is deficient in pre-rRNA processing such that the initial 35S pre-rRNA processing is blocked and 20S pre-rRNA is nearly absent. The reduced amount of 20S pre-rRNA leads to a shortage of 18S rRNA and is reflected in a change in the distribution of 60S and 40S ribosomal subunits; there is no free pool of 40S subunits, and the free pool of 60S subunits is greatly increased in size. The lack of free 40S subunits or the improper assembly of these subunits causes the nsr1 mutant to show sensitivity to the antibiotic paromomycin, which affects protein translation, at concentrations that do not affect the growth of the wild-type strain. Our data support the idea that NSR1 is involved in the proper assembly of pre-rRNA particles, possibly by bringing rRNA and ribosomal proteins together by virtue of its nuclear localization sequence-binding domain and multiple RNA recognition motifs. Alternatively, NSR1 may also act to regulate the nuclear entry of ribosomal proteins required for proper assembly of pre-rRNA particles.

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TGFβ/Activin signalling is required for ribosome biogenesis and cell growth in Drosophila salivary glands

Open Biology ◽

10.1098/rsob.160258 ◽

2017 ◽

Vol 7 (1) ◽

pp. 160258 ◽

Cited By ~ 5

Author(s):

Torcato Martins ◽

Nadia Eusebio ◽

Andreia Correia ◽

Joana Marinho ◽

Fernando Casares ◽

...

Keyword(s):

Cell Growth ◽

Salivary Glands ◽

Ribosomal Proteins ◽

Ribosome Biogenesis ◽

Growth Control ◽

Tissue Growth ◽

Cellular Growth ◽

Nucleolar Structure ◽

Cell Growth And Proliferation ◽

Tgfβ Superfamily

Signalling by TGFβ superfamily factors plays an important role in tissue growth and cell proliferation. In Drosophila , the activity of the TGFβ/Activin signalling branch has been linked to the regulation of cell growth and proliferation, but the cellular and molecular basis for these functions are not fully understood. In this study, we show that both the RII receptor Punt (Put) and the R-Smad Smad2 are strongly required for cell and tissue growth. Knocking down the expression of Put or Smad2 in salivary glands causes alterations in nucleolar structure and functions. Cells with decreased TGFβ/Activin signalling accumulate intermediate pre-rRNA transcripts containing internal transcribed spacer 1 regions accompanied by the nucleolar retention of ribosomal proteins. Thus, our results show that TGFβ/Activin signalling is required for ribosomal biogenesis, a key aspect of cellular growth control. Importantly, overexpression of Put enhanced cell growth induced by Drosophila Myc, a well-characterized inducer of nucleolar hypertrophy and ribosome biogenesis.

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