Tuning the ribosome: The influence of rRNA modification on eukaryotic ribosome biogenesis and function

Gene expression is an essential process for cellular growth, proliferation, and differentiation. The transcription of protein-coding genes and non-coding loci depends on RNA polymerases. Interestingly, numerous loci encode long non-coding (lnc)RNA transcripts that are transcribed by RNA polymerase II (RNAPII) and fine-tune the RNA metabolism. The nucleolus is a prime example of how different lncRNA species concomitantly regulate gene expression by facilitating the production and processing of ribosomal (r)RNA for ribosome biogenesis. Here, we summarise the current findings on how RNAPII influences nucleolar structure and function. We describe how RNAPII-dependent lncRNA can both promote nucleolar integrity and inhibit ribosomal (r)RNA synthesis by modulating the availability of rRNA synthesis factors in trans. Surprisingly, some lncRNA transcripts can directly originate from nucleolar loci and function in cis. The nucleolar intergenic spacer (IGS), for example, encodes nucleolar transcripts that counteract spurious rRNA synthesis in unperturbed cells. In response to DNA damage, RNAPII-dependent lncRNA originates directly at broken ribosomal (r)DNA loci and is processed into small ncRNA, possibly to modulate DNA repair. Thus, lncRNA-mediated regulation of nucleolar biology occurs by several modes of action and is more direct than anticipated, pointing to an intimate crosstalk of RNA metabolic events.

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Ubiquitin and Ubiquitin-Like Proteins and Domains in Ribosome Production and Function: Chance or Necessity?

International Journal of Molecular Sciences ◽

10.3390/ijms22094359 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4359

Author(s):

Sara Martín-Villanueva ◽

Gabriel Gutiérrez ◽

Dieter Kressler ◽

Jesús de la Cruz

Keyword(s):

Ribosomal Proteins ◽

Ribosome Biogenesis ◽

Ribosome Assembly ◽

Cellular Processes ◽

Substrate Protein ◽

Precursor Proteins ◽

Assembly Factors ◽

Ubiquitin Moiety ◽

And Function

Ubiquitin is a small protein that is highly conserved throughout eukaryotes. It operates as a reversible post-translational modifier through a process known as ubiquitination, which involves the addition of one or several ubiquitin moieties to a substrate protein. These modifications mark proteins for proteasome-dependent degradation or alter their localization or activity in a variety of cellular processes. In most eukaryotes, ubiquitin is generated by the proteolytic cleavage of precursor proteins in which it is fused either to itself, constituting a polyubiquitin precursor, or as a single N-terminal moiety to ribosomal proteins, which are practically invariably eL40 and eS31. Herein, we summarize the contribution of the ubiquitin moiety within precursors of ribosomal proteins to ribosome biogenesis and function and discuss the biological relevance of having maintained the explicit fusion to eL40 and eS31 during evolution. There are other ubiquitin-like proteins, which also work as post-translational modifiers, among them the small ubiquitin-like modifier (SUMO). Both ubiquitin and SUMO are able to modify ribosome assembly factors and ribosomal proteins to regulate ribosome biogenesis and function. Strikingly, ubiquitin-like domains are also found within two ribosome assembly factors; hence, the functional role of these proteins will also be highlighted.

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Expanding Role of Ubiquitin in Translational Control

International Journal of Molecular Sciences ◽

10.3390/ijms21031151 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1151 ◽

Cited By ~ 3

Author(s):

Shannon E. Dougherty ◽

Austin O. Maduka ◽

Toshifumi Inada ◽

Gustavo M. Silva

Keyword(s):

Translational Control ◽

Ribosomal Proteins ◽

Ribosome Biogenesis ◽

Rna Binding ◽

Protein Quality ◽

Rna Binding Proteins ◽

Ubiquitin Chain ◽

Molecular Aspects ◽

And Function

The eukaryotic proteome has to be precisely regulated at multiple levels of gene expression, from transcription, translation, and degradation of RNA and protein to adjust to several cellular conditions. Particularly at the translational level, regulation is controlled by a variety of RNA binding proteins, translation and associated factors, numerous enzymes, and by post-translational modifications (PTM). Ubiquitination, a prominent PTM discovered as the signal for protein degradation, has newly emerged as a modulator of protein synthesis by controlling several processes in translation. Advances in proteomics and cryo-electron microscopy have identified ubiquitin modifications of several ribosomal proteins and provided numerous insights on how this modification affects ribosome structure and function. The variety of pathways and functions of translation controlled by ubiquitin are determined by the various enzymes involved in ubiquitin conjugation and removal, by the ubiquitin chain type used, by the target sites of ubiquitination, and by the physiologic signals triggering its accumulation. Current research is now elucidating multiple ubiquitin-mediated mechanisms of translational control, including ribosome biogenesis, ribosome degradation, ribosome-associated protein quality control (RQC), and redox control of translation by ubiquitin (RTU). This review discusses the central role of ubiquitin in modulating the dynamism of the cellular proteome and explores the molecular aspects responsible for the expanding puzzle of ubiquitin signals and functions in translation.

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Functional ribosome biogenesis is a prerequisite for p53 destabilization: impact of chemotherapy on nucleolar functions and RNA metabolism

Biological Chemistry ◽

10.1515/hsz-2013-0153 ◽

2013 ◽

Vol 394 (9) ◽

pp. 1133-1143 ◽

Cited By ~ 17

Author(s):

Kaspar Burger ◽

Dirk Eick

Keyword(s):

Ribosomal Rna ◽

Ribosome Biogenesis ◽

Rna Metabolism ◽

Chemotherapeutic Drugs ◽

Tumor Suppressor P53 ◽

Nucleolar Structure ◽

Highly Sensitive ◽

Important Regulator ◽

Sensitive Sensor ◽

And Function

Abstract The production and processing of ribosomal RNA is a complex and well-coordinated nucleolar process for ribosome biogenesis. Progress in understanding nucleolar structure and function has lead to the unexpected discovery of the nucleolus as a highly sensitive sensor of cellular stress and an important regulator of the tumor suppressor p53. Inhibition of ribosomal RNA metabolism has been shown to activate a signaling pathway for p53 induction. This review elucidates the potential of classical and recently developed chemotherapeutic drugs to stabilize p53 by inhibiting nucleolar functions.

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Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function

Growth Factors ◽

10.1080/08977190701779101 ◽

2007 ◽

Vol 25 (4) ◽

pp. 209-226 ◽

Cited By ~ 155

Author(s):

Katarzyna Jastrzebski ◽

Katherine M. Hannan ◽

Elissaveta B. Tchoubrieva ◽

Ross D. Hannan ◽

Richard B. Pearson

Keyword(s):

Ribosomal Protein ◽

Ribosome Biogenesis ◽

S6 Kinase ◽

Coordinate Regulation ◽

Ribosomal Protein S6 ◽

And Function ◽

Kinase A ◽

Ribosomal Protein S6 Kinase

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Structure and function of ribosomal RNA gene chromatin

Biochemical Society Transactions ◽

10.1042/bst0360619 ◽

2008 ◽

Vol 36 (4) ◽

pp. 619-624 ◽

Cited By ~ 40

Author(s):

Joanna L. Birch ◽

Joost C.B.M. Zomerdijk

Keyword(s):

Ribosomal Rna ◽

Ribosome Biogenesis ◽

Rna Polymerase I ◽

Rrna Genes ◽

Rrna Gene ◽

Pol I ◽

And Function ◽

Polymerase I ◽

Cell Growth And Proliferation ◽

Cellular Control

Transcription of the major ribosomal RNAs by Pol I (RNA polymerase I) is a key determinant of ribosome biogenesis, driving cell growth and proliferation in eukaryotes. Hundreds of copies of rRNA genes are present in each cell, and there is evidence that the cellular control of Pol I transcription involves adjustments to the number of rRNA genes actively engaged in transcription, as well as to the rate of transcription from each active gene. Chromatin structure is inextricably linked to rRNA gene activity, and the present review highlights recent advances in this area.

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Faculty Opinions recommendation of RNA chaperones stimulate formation and yield of the U3 snoRNA-Pre-rRNA duplexes needed for eukaryotic ribosome biogenesis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1162632.624200 ◽

2009 ◽

Author(s):

Jonathan R Warner

Keyword(s):

Ribosome Biogenesis ◽

Eukaryotic Ribosome ◽

U3 Snorna ◽

Rna Chaperones

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Halofuginone triggers a transcriptional program centered on ribosome biogenesis and function in honey bees

Insect Biochemistry and Molecular Biology ◽

10.1016/j.ibmb.2021.103667 ◽

2021 ◽

pp. 103667

Author(s):

Melissa E. Flores ◽

Nora K. McNamara-Bordewick ◽

Natalie L. Lovinger ◽

Jonathan W. Snow

Keyword(s):

Honey Bees ◽

Ribosome Biogenesis ◽

Transcriptional Program ◽

And Function

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2′-O-Methylation of Ribosomal RNA: Towards an Epitranscriptomic Control of Translation?

Biomolecules ◽

10.3390/biom8040106 ◽

2018 ◽

Vol 8 (4) ◽

pp. 106 ◽

Cited By ~ 29

Author(s):

Piero Monaco ◽

Virginie Marcel ◽

Jean-Jacques Diaz ◽

Frédéric Catez

Keyword(s):

Ribosomal Rna ◽

Translational Control ◽

Ribosome Biogenesis ◽

In Vitro Translation ◽

Ribosome Structure ◽

Quantitative Mapping ◽

And Function ◽

The Impact ◽

First Time

Ribosomal RNA (rRNA) undergoes post-transcriptional modification of over 200 nucleotides, predominantly 2′-O-methylation (2′-O-Me). 2′-O-Methylation protects RNA from hydrolysis and modifies RNA strand flexibility but does not contribute to Watson-Crick base pairing. The contribution of 2′-O-Me to the translational capacity of ribosomes has been established. Yet, how 2′-O-Me participates in ribosome biogenesis and ribosome functioning remains unclear. The development of 2′-O-Me quantitative mapping methods has contributed to the demonstration that these modifications are not constitutive but rather provide heterogeneity to the ribosomal population. Moreover, recent advances in ribosome structure analysis and in vitro translation assays have proven, for the first time, that 2′-O-Me contributes to regulating protein synthesis. This review highlights the recent data exploring the impact of 2′-O-Me on ribosome structure and function, and the emerging idea that the rRNA epitranscriptome is involved in translational control.

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