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. 2020 Apr 29;48(2):595-612.
doi: 10.1042/BST20190854.

MicroRNAs and Long Non-Coding RNAs as Novel Regulators of Ribosome Biogenesis

Affiliations
Free PMC article

MicroRNAs and Long Non-Coding RNAs as Novel Regulators of Ribosome Biogenesis

Mason A McCool et al. Biochem Soc Trans. .
Free PMC article

Abstract

Ribosome biogenesis is the fine-tuned, essential process that generates mature ribosomal subunits and ultimately enables all protein synthesis within a cell. Novel regulators of ribosome biogenesis continue to be discovered in higher eukaryotes. While many known regulatory factors are proteins or small nucleolar ribonucleoproteins, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) are emerging as a novel modulatory layer controlling ribosome production. Here, we summarize work uncovering non-coding RNAs (ncRNAs) as novel regulators of ribosome biogenesis and highlight their links to diseases of defective ribosome biogenesis. It is still unclear how many miRNAs or lncRNAs are involved in phenotypic or pathological disease outcomes caused by impaired ribosome production, as in the ribosomopathies, or by increased ribosome production, as in cancer. In time, we hypothesize that many more ncRNA regulators of ribosome biogenesis will be discovered, which will be followed by an effort to establish connections between disease pathologies and the molecular mechanisms of this additional layer of ribosome biogenesis control.

Keywords: cancer; gene regulation; non-coding RNA; nucleolus; ribosomopathies.

Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. Ribosome biogenesis is regulated at multiple steps by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs).
The pre-rRNA is transcribed by RNAPI (red) and the 5S rRNA is transcribed by RNAPIII (blue). Pre-rRNA is processed in a series of steps to remove the external and internal transcribed spacer sequences (5′ ETS and 3′ ETS; ITS1 and ITS2). The rRNAs are assembled with ribosomal proteins (RPs) with assistance from assembly factors (AFs) to make the mature 40S ribosomal subunit (in red; 18S rRNA) and 60S ribosomal subunit (in blue; 28S, 5.8S and 5S rRNAs) to translate mRNAs in the cytoplasm. Control by the indicated miRNAs (left) and lncRNAs (right) can activate (green pointed arrow) or inhibit (red bar-headed arrow) specific steps in ribosome biogenesis.
Figure 2.
Figure 2.. Biogenesis and function of microRNAs (miRNAs).
(A) Canonical generation and activation of cellular miRNAs. In most cases, a primary miRNA transcript (pri-miRNA) containing the mature miRNA sequence is synthesized by RNAPII from a miRNA gene. Nuclear processing of the pri-miRNA by a microprocessor complex containing Drosha and DGCR8 results in a trimmed intermediate precursor hairpin (pre-miRNA), which is exported to the cytoplasm for secondary processing by Dicer endonuclease to generate the mature miRNA duplex. Argonaute (AGO) protein binds the miRNA duplex to form an active RNA-induced silencing complex (RISC), retaining the ‘guide' strand and expelling the ‘passenger' strand (miRNA*) for degradation. Guide strand choice depends on conformational energetics of loading the mature duplex into Argonaute. (B) miRNA-mediated post-transcriptional mRNA regulation depends on target complementarity. The active silencing complex is targeted to mRNA transcripts via complementary hybridization with the 6-base seed region of the loaded miRNA guide, usually at a site within the 3′UTR of the targets downstream of the coding sequence (brown). Based on the degree of miRNA:mRNA complementarity, RISC can induce translational repression, transcript destabilization, or transcript cleavage, thereby down-regulating target expression post-transcriptionally. Low complementarity causes mRNA poly(A) deadenylation and reduces translation efficiency, while high complementarity can trigger endonucleolytic target degradation (slicing). (C) rRNA-hosted miRNAs are stably generated and control diverse cellular processes and outcomes. Small rDNA-derived RNAs or rRNA-hosted miRNA analogs (srRNAs or rmiRNAs) are produced from functional (18S and 28S) and nonfunctional (5′ ETS) regions of the 47S pre-rRNA transcript. The mechanisms for rmiRNA production are poorly understood, but are not likely to be due to random degradation. Mature rmiRNAs have been observed to control diverse developmental, metabolic, and stress pathways.
Figure 3.
Figure 3.. Examples of miRNA-mediated control of ribosome biogenesis.
(A) hsa-miR-504 regulates TP53 levels and pre-rRNA transcription. miR-504 is generated from an FGF13 intron (exons in brown, miR-504 mirtron in green) and targets TP53 transcripts. Through an uninvestigated mechanism, TP53 protein dampens constitutive transcription of the FGF13/MIR504 locus. FGF13 up-regulation increases levels of miR-504 and the nucleolar protein isoform FGF13 1A, repressing TP53 translation and pre-rRNA transcription. This results in attenuation of global translation, reduction in oncogenic proteotoxic and oxidative stress, and decreased tumor cell apoptosis. (B) RPL5, RPL11, and RPS14 enable miRNA silencing of MYC. RPL5, RPL11, and RPS14 (blue) can bind the 3′UTR of MYC transcripts, and can guide active RISC complexes (yellow) loaded with miRNAs targeting MYC (green) to the mRNA. This RP-guided, miRNA-mediated MYC repression modulates cell cycle progression and proliferation, and attenuates ribosome biogenesis indirectly. (C) hsa-miR-10a enhances RP translation efficiency by binding 5′TOP mRNAs. miR-10a (green) was found to bind the 5′UTR of at least five small and four large RP mRNAs containing a 5′TOP motif (blue), increasing their translation efficiency. Augmented RP production enhances the cellular capacity for ribosome biogenesis and proliferation.
Figure 4.
Figure 4.. Biogenesis of diverse long non-coding RNAs (lncRNAs) involved in ribosome biogenesis.
(A) lncRNAs involved in ribosome biogenesis transcribed from ribosomal DNA (rDNA) gene loci. (Left) Intergenic spacer (IGS) RNAs are transcribed by RNA polymerase I (RNAPI) under stress conditions and processed into functional RNAs. (Middle) pre-rRNA transcription is controlled by growth factors and available energy regulated by several signaling pathways. (Right) Promoter and pre-rRNA antisense (PAPAS) RNAs are transcribed in an antisense orientation relative to the rDNA and rDNA promoter sequences and processed into functional RNAs. (B) lncRNAs involved in ribosome biogenesis transcribed by RNAPII in a variety of genomic contexts. (Left) lncRNAs are transcribed by RNAPII either independently long intergenic noncoding RNAs (lincRNAs) or via alternative splicing of other RNAPII transcripts. These RNAs can include small nucleolar RNA (snoRNA) sequences (gray) that form mature noncanonical C/D or H/ACA box small nucleolar ribonucleoproteins (snoRNPs) or binding motifs (blue). (Middle) RNAPII transcribes pre-mRNAs that can undergo back-splicing of exons to produce circular RNAs (circRNAs) (green). These RNAs can then contain motifs (blue) to bind and sequester proteins (blue-gray). (Right) Antisense lncRNAs are transcribed by RNAPII in the opposite direct of their sense transcript partners to regulate translation of specific, usually sense, transcript mRNAs (red).
Figure 5.
Figure 5.. Examples of molecular mechanisms of long non-coding RNAs (lncRNAs) involved in ribosome biogenesis.
(A) Long nucleolar RNA (LoNA) is a multifunctional polyadenylated lncRNA that regulates pre-rRNA transcription, modification, and processing. (Left) It contains two nucleolin binding sequences (blue), one of which is functional to bind and inhibit nucleolin (blue) function. (Right) It contains two C/D box small nucleolar RNA (snoRNA) sequences that are able to form noncanonical C/D box small nucleolar ribonucleoproteins (snoRNPs) (gray) to inhibit modification and processing of the pre-rRNA. (B) pRNA is a multifunctional lncRNA that regulates ribosomal DNA (rDNA) chromatin modifications. (Left) It forms a DNA:RNA triple helix with the T0 element of the rDNA promoter to recruit the chromatin modifier DNMT3b (brown) to methylate CpG (black). (Right) It contains a stem-loop structure that interacts with TIP5 (gray) the large subunit of the nucleolar remodeling complex (NoRC) (brown) to promote H3K9me3 histone methylations (red), remove H4ac acetylation modifications (blue), and cause a nucleosome shift to block rDNA promoter access. (C) circANRIL (green) binds PeBoW complex (PES1, BOP1, WDR12,) (green/blue) to inhibit pre-rRNA processing of internal transcribed spacer 2 (ITS2) through 47S homology domain (black).

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References

    1. Woolford J.L. Jr and Baserga S.J. (2013) Ribosome biogenesis in the yeast Saccharomyces cerevisiae. Genetics 195, 643–681 10.1534/genetics.113.153197 - DOI - PMC - PubMed
    1. Henras A.K., Plisson-Chastang C., O'Donohue M.F., Chakraborty A. and Gleizes P.E. (2015) An overview of pre-ribosomal RNA processing in eukaryotes. Wiley Interdiscip. Rev. RNA 6, 225–242 10.1002/wrna.1269 - DOI - PMC - PubMed
    1. Bartel D.P. (2018) Metazoan microRNAs. Cell 173, 20–51 10.1016/j.cell.2018.03.006 - DOI - PMC - PubMed
    1. Gebert L.F.R. and MacRae I.J. (2019) Regulation of microRNA function in animals. Nat. Rev. Mol. Cell Biol. 20, 21–37 10.1038/s41580-018-0045-7 - DOI - PMC - PubMed
    1. Lambert M., Benmoussa A. and Provost P. (2019) Small non-Coding RNAs derived from eukaryotic ribosomal RNA. Noncoding RNA 5, E16 10.3390/ncrna5010016 - DOI - PMC - PubMed
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