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Regulation of ribosomal protein genes: An ordered anarchy

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Abstract Ribosomal protein genes are among the most highly expressed genes in most cell types. Their products are generally essential for ribosome synthesis, which is the cornerstone for cell growth and proliferation. Many cellular resources are dedicated to producing ribosomal proteins and thus this process needs to be regulated in ways that carefully balance the supply of nascent ribosomal proteins with the demand for new ribosomes. Ribosomal protein genes have classically been viewed as a uniform interconnected regulon regulated in eukaryotic cells by target of rapamycin and protein kinase A pathway in response to changes in growth conditions and/or cellular status. However, recent literature depicts a more complex picture in which the amount of ribosomal proteins produced varies between genes in response to two overlapping regulatory circuits. The first includes the classical general ribosome‐producing program and the second is a gene‐specific feature responsible for fine‐tuning the amount of ribosomal proteins produced from each individual ribosomal gene. Unlike the general pathway that is mainly controlled at the level of transcription and translation, this specific regulation of ribosomal protein genes is largely achieved through changes in pre‐mRNA splicing efficiency and mRNA stability. By combining general and specific regulation, the cell can coordinate ribosome production, while allowing functional specialization and diversity. Here we review the many ways ribosomal protein genes are regulated, with special focus on the emerging role of posttranscriptional regulatory events in fine‐tuning the expression of ribosomal protein genes and its role in controlling the potential variation in ribosome functions. This article is categorized under: Translation > Ribosome Biogenesis Translation > Ribosome Structure/Function Translation > Translation Regulation
Ribosomal protein gene structure and distribution in the main kingdoms of life. (a) The number of ribosomal protein genes increases in duplicated genomes independent of the protein number and genome size. Genome sizes in mega bases (Mb) are illustrated based on data from NCBI genome browser overview tool for over 300 genomes per kingdom with the median size, the median number of ribosomal protein (RP) and RP genes (RPGs) calculated from 3 to 14 species per kingdom based on information taken from Ribosomal Protein Gene Database. Kingdoms with most genome duplication events are underlined. (b) General features of the different classes of RPGs. The most common structure of RPGs in a representative species from each of the six kingdoms of life are schematically illustrated to indicate the differences in gene size, regulatory region, and the gene organization in the genome. Green boxes, orange lines, gray lines, and blue lines represent the open reading frame (ORF), the introns, the intergenic sequences, 5′ and 3′ UTRs, respectively. The median size of the genes (bp) and ORFs are based on data from NCBI genome browser, SGD, Ribosomal Protein Gene Database, and ThaleMine (Yoshihama et al., 2002). The median number of introns per RPGs are illustrated on each schematic, while the median sizes (bp) of UTRs, ORF and introns are shown on top. Two or more copies of the same genes are shown for species with documented genome duplication events and pseudogenes are represented by green stripped boxes. In most cases the regulatory sequences (UTRs and introns) often vary between species, between genes, and even between duplicated genes. The UTR and gene sizes for archaea and bacteria are estimates based on limited number of genes that are likely to vary as more accurate mapping of the untranslated regions in these species becomes available. The transcription start sites are shown by the gray arrows on top
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General mechanisms for controlling and coordinating the expression of RPGs. The illustrated schematics depict the basic principles guiding the control of RPG expression. In this hypothetical model, the RPGs will respond collectively to changes in the amount of mature rRNA and signals for global repression of ribosome synthesis transcription repression guided by common promoter elements. On the other hand, gene specific regulation required for adjusting the dose of duplicated RPGs and genes playing extra‐ribosomal roles may take place through regulation of splicing, RNA stability, transcription termination, and translation. A, P, and U indicates examples of modifications of RPs through acetylation, phosphorylation, and ubiquitination
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Strategies of interparalog regulation in yeast. Schematic representation of different regulatory elements controlling the expression of dRPGs and their relative contribution to the hierarchy of RPGs in Saccharomyces cerevisiae. In this model, the transcription of duplicated genes does not reflect their final expression outcome. Instead, it is the difference in splicing efficiency of the paralog's pre‐mRNA enforced by asymmetric feedback mechanism differentially inhibiting the splicing of the minor paralog that mostly determine the hierarchy of paralog expression. Differential translation of the major paralog further widens the gap between the two paralogs by favoring the synthesis of the major paralog mRNA. In some isolated cases, differential integration of the major paralog protein into ribosomes also occurs. When cells are exposed to stress or run out of nutrients, the major paralogs are differentially repressed at the level of splicing and translation, tipping the balance toward the production of ribosomes with the minor paralogs, which are in general less affected by stress and starvation. In the cases of duplicated genes lacking introns, most of the regulation takes place through the 5′ and 3′ UTRs that are often different in sequence and length leading to alternative transcription termination, stability and translation efficiency. TSS, TTS, E1, I, E2, 5′ UTR, 3′ UTR indicate transcription starts site, TTS, Exon 1, Intron, Exon 2, 5′ untranslated region, 3′ untranslated region
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Mechanisms of regulation of ribosomal protein expression. The different levels of regulation modulating the expression of RPGs in yeast and human cells are outlined. Mechanisms lacking direct experimental evidence are indicated with question marks. The diagram summarizes factors found in different genes. Not all the factors are found at the same time and on the same genes. PTC, PIC, NMD, EJC, Upf, RP, KS, SC, and UL indicate premature termination codon, preinitiation complex, nonsense mediated decay, exon junction complex, UPF complex required for RNA degradation via NMD, ribosomal protein, suboptimal Kozak score, suboptimal codon, and long 3′ untranslated region, respectively
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Translation > Translation Regulation
Translation > Ribosome Structure/Function
Translation > Ribosome Biogenesis

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