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The emerging role of triple helices in RNA biology

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The ability of RNA to form sophisticated secondary and tertiary structures enables it to perform a wide variety of cellular functions. One tertiary structure, the RNA triple helix, was first observed in vitro over 50 years ago, but biological activities for triple helices are only beginning to be appreciated. The recent determination of several RNA structures has implicated triple helices in distinct biological functions. For example, the SAM‐II riboswitch forms a triple helix that creates a highly specific binding pocket for S‐adenosylmethionine. In addition, a triple helix in the conserved pseudoknot domain of the telomerase‐associated RNA TER is essential for telomerase activity. A viral RNA cis‐acting RNA element called the ENE contributes to the nuclear stability of a viral noncoding RNA by forming a triple helix with the poly(A) tail. Finally, a cellular noncoding RNA, MALAT1, includes a triple helix at its 3′‐end that contributes to RNA stability, but surprisingly also supports translation. These examples highlight the diverse roles that RNA triple helices play in biology. Moreover, the dissection of triple helix mechanisms has the potential to uncover fundamental pathways in cell biology. WIREs RNA 2014, 5:15–29. doi: 10.1002/wrna.1194 This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry RNA Processing > 3' End Processing RNA Turnover and Surveillance > Regulation of RNA Stability

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U•A–U and C•G–C base triples. (a) U•A–U and (b) C•G–C base triples with the Hoogsteen and Watson‐Crick interactions shown. Hydrogen bonds are shown as broken lines. The cytosine N3 of the Hoogsteen interaction is in the protonated state to yield an additional hydrogen bond.
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The MALAT1 ENE‐like triple helix. (a) RNA processing pathway for MALAT1 and mascRNA. For simplicity, the polyadenylated species is shown as the primary transcript, but it is not clear whether the RNase P cleavage occurs on polyadenylated MALAT1 or co‐transcriptionally. The diagram is not to scale; the highlighted elements compose only a small fraction of the total MALAT1 length. The numbers refer to the human MALAT1, but all the relevant domains are conserved. (b) Secondary structure and triple helix formation in the MALAT1 ENE‐like element. The structure on the left corresponds to the full‐length human MALAT1 ENE‐like element, while the structure on the right is a minimal element derived from murine MALAT1, Comp14. The U‐rich sequence that forms Watson‐Crick base pairs is shown in red, the A‐rich stretch is orange, and the U‐rich tract that forms Hoogsteen base triples is yellow. The Hoogsteen interactions in the triple helix are shown with filled circles and Watson‐Crick base pairs or triples are depicted with solid lines; predicted A‐minor interactions are shown as dashed lines. The central C and G nucleotides are shown in light blue. The C•G–C is depicted as part of the helix based on pH profiles, but this triple was not observed in a structural model. The lower G–C stem is shown in dark blue. The sequences important for translation are highlighted in the green box.
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The PAN ENE triple helix. (a) Left Predicted secondary structure of the 79‐nt PAN ENE. The numbers are relative to the PAN RNA transcription start site; the polyadenylation site is at position 1077 (not shown). The upper and lower stems are colored in light blue and dark blue, respectively. The five‐uridine stretches that participate in the triple helix are shown in yellow and red. Right: Schematic of the triple helix formed by the core ENE in complex with oligoA9 (orange). The Hoogsteen interactions in the triple helix are shown with filled circles and Watson‐Crick base pairs are depicted with solid lines. A‐minor interactions are shown as dashed lines. (b) Surface representation of the PAN RNA ENE. Color‐coding is the same as in (a). All PAN RNA ENE structures were derived from PDB ID: 3P22. (c) The triple helix and lower stem of the PAN RNA ENE in complex with A2–A9 of oligoA9. The U•A–U triple helix and the interface of the A‐minor interactions between the minor groove of the lower G–C stem with A2‐A4 are indicated. A952‐U953 (gray) are ‘flipped out’ relative to the bases in the helix. (d) Close‐up view of the 3′‐most adenosine, A9 (orange, stick representation) as it fits in the pocket formed from the U‐rich strands (yellow and red, surface representation) and the upper stem (light blue, surface representation).
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The TER triple helix. (a) The secondary structure of the TER. The line drawing depicts the full‐length TER secondary structure and highlights the positions of the box H/ACA snoRNA‐like elements and the template. The sequence of the pseudoknot used for the NMR structure is also shown. Note that nt 121–165 were deleted in the structure determination of the pseudoknot. Watson‐Crick pairs are shown with solid lines and Hoogsteen or other tertiary interactions in the triple helix are shown with dotted lines. The three strands that compose the triple helix are colored in yellow, red, and orange. The U99A173 Hoogsteen base pair is light blue. (b) Surface representation of the TER pseudoknot. The three strands corresponding to the triple helix are colored as in (a). All structures for the TER pseudoknot were derived from PDB ID: 2 K95. (c) The TER triple helix including the conventional U•A–U triples at the bottom, the U99A173 Hoogsteen base pair, and the unconventional base triples at the top. The colors are the same as (a). (d) Base triples and hydrogen bonds between nonconventional triples at the top of the TER triple helix. Nitrogens are dark blue, oxygens are bright red, hydrogens are white, and carbons are color coded as in (a). Hydrogen bonds are shown as dashed lines.
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The SAM‐II triple helix. (a) Schematic depiction of the SAM‐II riboswitch structure. The triple helix is shown as yellow, red, and orange nucleotides. Watson‐Crick interactions are shown with solid lines whereas nonconventional and Hoogsteen base interactions within the triple helix are shown with solid circles. Tertiary interactions and nonconventional base pairs outside the triple helix are shown with dashed lines. SAM is blue (ASAM), and the Shine‐Delgarno sequence (A47‐G52) is shaded with a green box. (b) Surface representation of the SAM‐II riboswitch. The three strands corresponding to the triple helix and SAM are color coded as in (a). All structures for SAM‐II were from PDB ID: 2QWY. (c) Stick representation of the triple helix domain in the SAM‐II riboswitch showing the fit of SAM in the ligand‐binding pocket. The three strands corresponding to the triple helix and SAM are color coded as in (a). (d) Base triples and hydrogen bonds between the SAM‐II triple helix and the SAM adenosine. Nitrogens are dark blue, oxygens are bright red, hydrogens are white, carbons are color coded by triple helix strand as in (a). Hydrogen bonds are shown with dashed lines.
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RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry
RNA Processing > 3′ End Processing
RNA Turnover and Surveillance > Regulation of RNA Stability

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