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Structural architecture of the human long non-coding RNA, steroid receptor RNA activator.

Novikova IV, Hennelly SP, Sanbonmatsu KY - Nucleic Acids Res. (2012)

Bottom Line: Our experimental findings (SHAPE, in-line, DMS and RNase V1 probing) reveal that this lncRNA has a complex structural organization, consisting of four domains, with a variety of secondary structure elements.Rapid evolutionary stabilization of RNA structure, combined with frame-disrupting mutations in conserved regions, suggests that evolutionary pressure preserves the RNA structural core rather than its translational product.We perform similar experiments on alternatively spliced SRA isoforms to assess their structural features.

View Article: PubMed Central - PubMed

Affiliation: Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.

ABSTRACT
While functional roles of several long non-coding RNAs (lncRNAs) have been determined, the molecular mechanisms are not well understood. Here, we report the first experimentally derived secondary structure of a human lncRNA, the steroid receptor RNA activator (SRA), 0.87 kB in size. The SRA RNA is a non-coding RNA that coactivates several human sex hormone receptors and is strongly associated with breast cancer. Coding isoforms of SRA are also expressed to produce proteins, making the SRA gene a unique bifunctional system. Our experimental findings (SHAPE, in-line, DMS and RNase V1 probing) reveal that this lncRNA has a complex structural organization, consisting of four domains, with a variety of secondary structure elements. We examine the coevolution of the SRA gene at the RNA structure and protein structure levels using comparative sequence analysis across vertebrates. Rapid evolutionary stabilization of RNA structure, combined with frame-disrupting mutations in conserved regions, suggests that evolutionary pressure preserves the RNA structural core rather than its translational product. We perform similar experiments on alternatively spliced SRA isoforms to assess their structural features.

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Sequence alignment for the highly conserved SRA regions. (A) SRA conservation diagram for helices H12 and H13 of domain II (nucleotide positions 357–440). Left, secondary structure. Annotation is as in Figure 4. Right, sequence alignment across 45 vertebrates. Top line shows dot-bracket notation of secondary structure. Light blue, complementarity of helix H12; light brown and light green, complementarity of helix H13. Red, covariant base pairs. (B) Same as (A) for H15–H18 of domain III (nucleotide positions 478–583).
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gks071-F5: Sequence alignment for the highly conserved SRA regions. (A) SRA conservation diagram for helices H12 and H13 of domain II (nucleotide positions 357–440). Left, secondary structure. Annotation is as in Figure 4. Right, sequence alignment across 45 vertebrates. Top line shows dot-bracket notation of secondary structure. Light blue, complementarity of helix H12; light brown and light green, complementarity of helix H13. Red, covariant base pairs. (B) Same as (A) for H15–H18 of domain III (nucleotide positions 478–583).

Mentions: The most striking feature of the lncRNA secondary structure is the local region of domain III, occupying positions 493–586 and comprising a three-way junction branching helices H15, H16 and H17 (detailed alignment can be found in Figure 5). This RNA segment could be important functionally, as 57% of the nucleotides in this region are 100% conserved across vertebrates, from platypus to human.Figure 5.


Structural architecture of the human long non-coding RNA, steroid receptor RNA activator.

Novikova IV, Hennelly SP, Sanbonmatsu KY - Nucleic Acids Res. (2012)

Sequence alignment for the highly conserved SRA regions. (A) SRA conservation diagram for helices H12 and H13 of domain II (nucleotide positions 357–440). Left, secondary structure. Annotation is as in Figure 4. Right, sequence alignment across 45 vertebrates. Top line shows dot-bracket notation of secondary structure. Light blue, complementarity of helix H12; light brown and light green, complementarity of helix H13. Red, covariant base pairs. (B) Same as (A) for H15–H18 of domain III (nucleotide positions 478–583).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3367176&req=5

gks071-F5: Sequence alignment for the highly conserved SRA regions. (A) SRA conservation diagram for helices H12 and H13 of domain II (nucleotide positions 357–440). Left, secondary structure. Annotation is as in Figure 4. Right, sequence alignment across 45 vertebrates. Top line shows dot-bracket notation of secondary structure. Light blue, complementarity of helix H12; light brown and light green, complementarity of helix H13. Red, covariant base pairs. (B) Same as (A) for H15–H18 of domain III (nucleotide positions 478–583).
Mentions: The most striking feature of the lncRNA secondary structure is the local region of domain III, occupying positions 493–586 and comprising a three-way junction branching helices H15, H16 and H17 (detailed alignment can be found in Figure 5). This RNA segment could be important functionally, as 57% of the nucleotides in this region are 100% conserved across vertebrates, from platypus to human.Figure 5.

Bottom Line: Our experimental findings (SHAPE, in-line, DMS and RNase V1 probing) reveal that this lncRNA has a complex structural organization, consisting of four domains, with a variety of secondary structure elements.Rapid evolutionary stabilization of RNA structure, combined with frame-disrupting mutations in conserved regions, suggests that evolutionary pressure preserves the RNA structural core rather than its translational product.We perform similar experiments on alternatively spliced SRA isoforms to assess their structural features.

View Article: PubMed Central - PubMed

Affiliation: Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.

ABSTRACT
While functional roles of several long non-coding RNAs (lncRNAs) have been determined, the molecular mechanisms are not well understood. Here, we report the first experimentally derived secondary structure of a human lncRNA, the steroid receptor RNA activator (SRA), 0.87 kB in size. The SRA RNA is a non-coding RNA that coactivates several human sex hormone receptors and is strongly associated with breast cancer. Coding isoforms of SRA are also expressed to produce proteins, making the SRA gene a unique bifunctional system. Our experimental findings (SHAPE, in-line, DMS and RNase V1 probing) reveal that this lncRNA has a complex structural organization, consisting of four domains, with a variety of secondary structure elements. We examine the coevolution of the SRA gene at the RNA structure and protein structure levels using comparative sequence analysis across vertebrates. Rapid evolutionary stabilization of RNA structure, combined with frame-disrupting mutations in conserved regions, suggests that evolutionary pressure preserves the RNA structural core rather than its translational product. We perform similar experiments on alternatively spliced SRA isoforms to assess their structural features.

Show MeSH
Related in: MedlinePlus