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Making ends meet: New functions of mRNA secondary structure

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Abstract The 5′ cap and 3′ poly(A) tail of mRNA are known to synergistically regulate mRNA translation and stability. Recent computational and experimental studies revealed that both protein‐coding and non‐coding RNAs will fold with extensive intramolecular secondary structure, which will result in close distances between the sequence ends. This proximity of the ends is a sequence‐independent, universal property of most RNAs. Only low‐complexity sequences without guanosines are without secondary structure and exhibit end‐to‐end distances expected for RNA random coils. The innate proximity of RNA ends might have important biological implications that remain unexplored. In particular, the inherent compactness of mRNA might regulate translation initiation by facilitating the formation of protein complexes that bridge mRNA 5′ and 3′ ends. Additionally, the proximity of mRNA ends might mediate coupling of 3′ deadenylation to 5′ end mRNA decay. This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems Translation > Translation Regulation
Intramolecular basepairing brings the ends of RNA close. (a) and (b) Show the secondary structure of the human MIF mRNA as predicted and drawn using the RNAstructure software package (https://rna.urmc.rochester.edu/RNAstructure.html). (a) Shows a circular diagram where the sequence is clockwise around the outside of the circle, with the 5′ and 3′ ends at the top of the circle. Blue lines are basepairs; the weight of a blue line represents the estimated pairing probability in the Boltzmann ensemble, where heavier lines are higher estimated probabilities. (b) Shows a collapsed diagram of one secondary structure in the ensemble, where basepairs are colored according to estimated base pairing probabilities in the conformational ensemble. Both representations of the secondary structure demonstrate how basepairing brings the ends close. The probable helix close to the 5′ end and the probable stem‐loop at the 3′ end both serve to bring the ends together for this sequence. (c) Shows the FRET‐measured end‐to‐end distances as a function of sequence length. The colored dots are: yeast RPL41A mRNA (red), firefly luciferase mRNA (orange), rabbit β‐globin mRNA (magenta), human ATP5J2 mRNA (green), HSBP1 mRNA (indigo), MIF mRNA (blue), MRPL51 mRNA (gray), GAPDH mRNA (brown), HOTAIR lncRNA (purple), and NEAT1_S lncRNA (dark green). The black line is the end‐to‐end distance of a freely jointed RNA chain (Reprinted with permission from Lai et al. [2018]). FRET, Förster resonance energy transfer
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The intrinsic closeness of mRNA ends may augment translation by stabilizing the eIF4E•eIF4G•PABP complex
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The E. coli 16S rRNA sequence ends are far apart. This figure shows how a pseudoknot in the small subunit rRNA facilitates a longer end‐to‐end distance than we found in other ncRNA. In part, this exposes the anti‐Shine–Dalgarno sequence to base pairs with an mRNA Shine–Dalgarno sequence to initiate translation
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Histogram of end‐to‐end distances for human mRNAs and lncRNAs. (a) Distribution of estimated mRNA end‐to‐end distances for the HeLa cell transcriptome. (b) Distribution for human lncRNA sequences. N is the number of sequences analyzed (Reprinted with permission from Lai et al. [2018])
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smFRET shows that mRNAs fold into a dynamic ensemble of structures. The top plot shows the smFRET for the human GAPDH mRNA as a function of time where blue is fluorescence intensity of the donor (Cy3) at the 3′ end of the 3′ UTR and red is fluorescence intensity of the acceptor (Cy5) at the 5′ end of the 5′ UTR. The acceptor photobleaches at about 80 s. The bottom plot shows the FRET efficiency in black with an idealized model fit by a Hidden Markon Model in magenta, where fluctuation is shown between the 0.2, 0.4, and 0.8 FRET states that correspond to distinct end‐to‐end distances (Reprinted with permission from Lai et al. [2018]). smFRET, single‐molecule Förster resonance energy transfer
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Translation > Translation Regulation
RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems
RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry

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