Multiple information carried by RNAs: total eclipse or a light at the end of the tunnel?

Figures & data

Table 1. Examples of RNAs with dual functions

Organism	Type	Role	Refs
Bacteria
RNAIII (S. aureus)	RNA	Modulates the production of toxins and enzymes by base-pairing on mRNA targets	[132]
	Protein	Controls the switch between early and late expression of several exotoxins	[133]
SgrS (E. coli)	RNA	Regulate sugar stress (prolonged stress)	[134]
	Protein	Regulate sugar stress (early response)	[134]
SR1 (Bacillus)	RNA	Regulation of arginine catabolism	[135]
	Protein	SR1P binds and stabilizes the gapA operon mRNAs	[135]
tmRNA (Bacteria)	RNA	Function as a tRNA by adding alanine to a stalled polypeptide chain	[135]
	Protein	Function as a mRNA by incorporating a degradation tag to the polypeptide chain	[135]
miPEP171b (M. truncatula)	RNA	Downregulates target genes involved in root development	[136]
	Protein	Enhances the accumulation of its corresponding mature miRNA	[136]
miPEP165a (A. thaliana)	RNA	Downregulates target genes involved in root development	[136]
	Protein	Enhances the accumulation of its corresponding mature miRNA	[136]
Plants
Enod40	RNA	Confers specificity for the recognition of mRNA targets of MtRBP1	[137]
	Protein	Affects MtRBP1 localization during nodule development	[137]
Insects
Oskar (Drosophila)	RNA	Scaffold for the complexes essential for development of the oocyte (early stage)	[138]
	Protein	Scaffold for the complexes essential for development of the oocyte (late stage)	[138]
Fish
Sqt (Danio rerio)	RNA	Deliver/sequester maternal factors for dorsal specification	[139]
	Protein	Deliver/sequester maternal factors for dorsal specification	[139]
Amphibians
VegT (Xenopus)	RNA	Organization of the cytokeratin cytoskeleton	[140]
	Protein	Transcription factor of the T-box family	[140]
Mammals (mainly human and mice)
p53	RNA	Stimulates p53 translation and prevents p53 protein from Mdm2-induced degradation	[115]
	Protein	Tumour suppressor	[115]
SRA1	RNA	Co-activator of transcription factors	[12]
	Protein	Inhibitor of the co-activation function of SRA RNA	[12]
circ-ZNF609	RNA	Serves as a sponge for miR-150-5p and controls cell proliferation	[141]
	Protein	Control of myoblast proliferation	[120]
ASCC3	RNA	Counteracts the function of the protein-coding isoform	[38]
	Protein	Negative regulator of the host defence response	[38]
LINC00961/SPAR	RNA	has as an anti-angiogenic role by inhibiting the function of Tβ4 protein	[108]
	Protein	Involved in muscle regeneration/has a pro-angiogenic role by binding the SYNE1 protein	[107]
HIC	RNA	Activates P-TEFb by displacing 7SK RNA	[142]
	Protein	Inhibits P-TEFb transcription	[143]
Irs-1	RNA	Inhibits myoblasts differentiation through complementary sequence to Rb mRNA	[144]
	Protein	Coordinates skeletal muscle growth and metabolism	[145]
apoE/apoE-I3	RNA	apoE-I3 controls apoE expression in neurons	[146]
	Protein	Involved in lipid transport system	[146]
PNUTS	RNA	regulates EMT migration and invasion in vitro through its miR-205 interaction	[39]
	Protein	functions as a proto-oncogene by sequestering PTEN	[147]

Figure 1. Diversification of proteomic and transcriptional outputs through constitutive or alternative splicing. More than 95% of introns are rapidly degraded after splicing (top left panel), but some can escape degradation and then represent precursors of short ncRNA [148] (top right panel). Retained introns can also favour the formation of protein isoforms (bottom left panel) or, if it disturbs the ORF, it can promote the formation of a long ncRNAs (bottom right panel). Exons and introns are represented by boxes and lines, respectively. mRNA, messenger RNA; ncRNA, non-coding RNA; H/ACA snoRNA, H/ACA box small nucleolar RNA; C/D snoRNA, C/D small nucleolar RNA

Table 2. Number of small ncRNAs identified in intronic regions of lncRNAs. All numbers were inferred from the DASHR database and were calculated from UCSC main table ‘Genes and Gene Predictions’ intersected with DASHR collection [46]. *, These intronic snoRNA are included in snoRNA host-genes (SNHG); miRNA, microRNA; rRNA, ribosomal RNA; scRNA, small cytoplasmic RNA; snoRNA, small nucleolar RNA; snRNA, small nuclear RNA; tRNA, transfer RNA

Type of ncRNA	Total number	Within intron of lncRNA	%
miRNA	1,582	198	12.51
rRNA	1,723	204	11.84
scRNA	1,291	170	13.17
snoRNA	402	88 *	21.89
snRNA	4,278	533	12.46
tRNA	623	52	8.35
		Mean:	13.37 ± 4.51

Figure 2. The 2ʹO-methylation of H. volcanii pre-tRNATrp is guided by its own intron. Thick arrows indicate the pre-tRNA^Trp processing pathway from nucleotide methylation and splicing to the production of a tRNA^Trp and the excised intron. RNP, ribonucleoprotein complex; C, cytosine; Cm, methylated cytosine; U, uracil; Um, methylated uracil. Adapted from [64]

Figure 3. The micropeptides Myoregulin (MLN) and Dwarf open reading frame (DWORF). DWARF RNA and MLN RNA were first identified as long non-coding RNAs (lncRNAs; Refseq numbers NR_037902 and BC069675 respectively). It appears that these two lncRNAs can encode DWORF and MLN micropeptides, respectively. Subsequently, their RefSeq category has been revised: NR_037902 became NM_001352129 and BC069675 were replaced by NM_001040109. DWORF and MLN are both involved in muscle contraction. The first one enables muscle relaxation by activating the SERCA calcium pump and thus the re-import of Ca2+ into the sarcoplasmic reticulum. Conversely, the second one maintains muscle contraction by preventing the re-import of Ca2+ by inhibiting the SERCA pump

Figure 4. The special case of group II self-catalytic introns. (A) In prokaryotes, group II introns are composed of several domains that confer their self-catalytic activity. Domains I to VI are hypothesized to have evolved into separate activities in eukaryotes, namely snRNAs and the IEP homolog, PRP8 protein. (B)In eukaryotes, splicing of introns requires distinct effector RNAs. Grey arrows represent the 2 steps of the splicing reaction i.e. the nucleophilic attack of the branch point A and of the free 3ʹOH of the exon. 5ʹ and 3ʹ stand for 5ʹ- and 3ʹ-ends of exon; IEP, intron-encoded proteins; ORF, open reading frame. Adapted from Vosseberg [127]

Novick RP, Ross HF, Projan SJ, et al. Synthesis of staphylococcal virulence factors is controlled by a regulatory RNA molecule. Embo J. 1993;12:3967–3975.

 PubMed Web of Science ®Google Scholar

Balaban N, Novick RP. Translation of RNAIII, the Staphylococcus aureus agr regulatory RNA molecule, can be activated by a 3ʹ-end deletion. FEMS Microbiol Lett. 1995;133:155–161.

 PubMed Web of Science ®Google Scholar

Vanderpool CK, Balasubramanian D, Lloyd CR. Dual-functionRNA regulators in bacteria. Biochimie. 2011;93:1943–1949.

 PubMed Web of Science ®Google Scholar

Gimpel M, Preis H, Barth E, et al. SR1–a small RNA with two remarkably conserved functions. Nucleic Acids Res. 2012;40:11659–11672.

 PubMed Web of Science ®Google Scholar

Lauressergues D, Couzigou JM, Clemente HS, et al. Primary transcripts of microRNAs encode regulatory peptides. Nature. 2015;520:90–93.

 PubMed Web of Science ®Google Scholar

Campalans A, Kondorosi A, Crespi M. Enod40, a short open reading frame-containing mRNA, induces cytoplasmic localization of a nuclear RNA binding protein in Medicago truncatula. Plant Cell. 2004;16:1047–1059.

 PubMed Web of Science ®Google Scholar

Rongo C, Gavis ER, Lehmann R. Localization of oskar RNA regulates oskar translation and requires Oskar protein. Development. 1995;121:2737–2746.

 PubMed Web of Science ®Google Scholar

Lim S, Kumari P, Gilligan P, et al. Dorsal activity of maternal squint is mediated by a non-coding function of the RNA. Development. 2012;139:2903–2915.

 PubMed Web of Science ®Google Scholar

Kloc M, Foreman V, Reddy SA. Binary function of mRNA. Biochimie. 2011;93:1955–1961.

 PubMed Web of Science ®Google Scholar

Candeias MM. The can and can’t dos of p53 RNA. Biochimie. 2011;93:1962–1965.

 PubMed Web of Science ®Google Scholar

Ulveling D, Francastel C, Hube F. When one is better than two: RNA with dual functions. Biochimie. 2011;93:633–644.

 PubMed Web of Science ®Google Scholar

Peng L, Chen G, Zhu Z, et al. Circular RNA ZNF609 functions as a competitive endogenous RNA to regulate AKT3 expression by sponging miR-150-5p in Hirschsprung’s disease. Oncotarget. 2017;8:808–818.

 PubMedGoogle Scholar

Legnini I, Di TG, Rossi F, et al. Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis. Mol Cell. 2017;66:22–37.

 PubMed Web of Science ®Google Scholar

Williamson L, Saponaro M, Boeing S, et al. UV irradiation induces a non-coding RNA that functionally opposes the protein encoded by the same gene. Cell. 2017;168:843–855.

 PubMed Web of Science ®Google Scholar

Spencer HL, Sanders R, Boulberdaa M, et al. The LINC00961 transcript and its encoded micropeptide, small regulatory polypeptide of amino acid response, regulate endothelial cell function. Cardiovasc Res. 2020;116:1–14.

 PubMed Web of Science ®Google Scholar

Matsumoto A, Pasut A, Matsumoto M, et al. mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. Nature. 2017;541:228–232.

 PubMed Web of Science ®Google Scholar

Young TM, Tsai M, Tian B, et al. Cellular mRNA activates transcription elongation by displacing 7SK RNA. PLoS One. 2007;2:e1010.

 PubMed Web of Science ®Google Scholar

Young TM, Wang Q, Pe’ery T, et al. The human I-mfa domain-containing protein, HIC, interacts with cyclin T1 and modulates P-TEFb-dependent transcription. Mol Cell Biol. 2003;23:6373–6384.

 PubMed Web of Science ®Google Scholar

Nagano H, Yamagishi N, Tomida C, et al. A novel myogenic function residing in the 5ʹ non-coding region of Insulin receptor substrate-1 (Irs-1) transcript. BMC Cell Biol. 2015;16:8.

 PubMedGoogle Scholar

Long YC, Cheng Z, Copps KD, et al. Insulin receptor substrates Irs1 and Irs2 coordinate skeletal muscle growth and metabolism via the Akt and AMPK pathways. Mol Cell Biol. 2011;31:430–441.

 PubMed Web of Science ®Google Scholar

Xu Q, Walker D, Bernardo A, et al. Intron-3 retention/splicing controls neuronal expression of apolipoprotein E in the CNS. J Neurosci. 2008;28:1452–1459.

 PubMed Web of Science ®Google Scholar

Grelet S, Link LA, Howley B, et al. A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression. Nat Cell Biol. 2017;19:1105–1115.

 PubMed Web of Science ®Google Scholar

Kavela S, Shinde SR, Ratheesh R, et al. PNUTS functions as a proto-oncogene by sequestering PTEN. Cancer Res. 2013;73:205–214.

 PubMed Web of Science ®Google Scholar

Roberts GC, Smith CW. Alternative splicing: combinatorial output from the genome. Curr Opin Chem Biol. 2002;6:375–383. We apologize to those whose works have not been cited in this article owing to lack of space.

 PubMed Web of Science ®Google Scholar

Leung YY, Kuksa PP, mlie-Wolf A, et al. DASHR: database of small human noncoding RNAs. Nucleic Acids Res. 2016;44:D216–D222.

 PubMed Web of Science ®Google Scholar

Singh SK, Gurha P, Tran EJ, et al. Sequential 2ʹ-O-methylation of archaeal pre-tRNATrp nucleotides is guided by the intron-encoded but trans-acting box C/D ribonucleoprotein of pre-tRNA. J Biol Chem. 2004;279:47661–47671.

 PubMed Web of Science ®Google Scholar

Vosseberg J, Snel B. Domestication of self-splicing introns during eukaryogenesis: the rise of the complex spliceosomal machinery. Biol Direct. 2017;12:30.

 PubMed Web of Science ®Google Scholar