Three studies have characterized the full complement of RNA folding in cells. They find large numbers of secondary structures in RNA, some of which may have functional consequences for the cell. See Letters p.696, p.701 & p.706
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Ramos, S., Laederach, A. A second layer of information in RNA. Nature 505, 621–622 (2014). https://doi.org/10.1038/505621a
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DOI: https://doi.org/10.1038/505621a
Donald Forsdyke
Further layers of information at the genome level?
Noting that the "chemical structure of RNA is analogous to that of DNA," Ramos and Laedereck (1) when writing on "a second layer of information in RNA" assume, like the three articles to which they refer, that the added layer relates to RNA structure and not to the potential of the duplex DNAs of the corresponding genes to extruded stem-loop structures. While, as all authors note, there are roles for mRNA structure in the regulation of transcription and translation, a "folding problem" is identified, "because mRNA must be unfolded to successfully act as a messenger."
Yet, why mRNAs burden themselves with so much unnecessary structure, was not considered. When this apparently excessive structure was discovered computationally in the 1990s, the question was addressed by examining introns and regions deemed extragenic (2-4). Compared with protein-encoding regions, this control revealed as much structure potential, and sometimes more (in the case of introns), in these DNA regions. Today it is appreciated that extragenic regions are transcribed (5), so a role of structure at the RNA level can still be entertained. However, there is growing evidence for profound function at the genomic level, be that genome DNA or RNA (6).
1. Ramos S. B. V., Laederach, A. Nature 505, 621-622 (2014).
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4. Forsdyke, D. R. J. Mol. Evol. 41, 573-581 (1995).
5. Ota et al. (2004) Nature Genetics 36, 40-45 (2004).
6. Forsdyke, D. R. Microbes Infect. paper here doi: 10.1016/j.micinf.2013.10.017 (in press 2114).
Alain Laederach
The results reported in the three articles mentioned here do not claim that the structure of the genome at the DNA is more or less relevant to regulation than that of RNA, simply that it is another layer of regulation available to the cell. The relative importance of RNA vs. DNA structure is likely to be context specific, depending on which molecular mechanism was ultimately selected for. What is important with these three studies is that all mRNAs fold into complex structures if given the opportunity (e.g. in vitro). There is nothing about their sequence which selects against structure. The cell has evolved mechanisms to overcome these folded structures if they are deleterious to function. In other cases, these structures are integral to the biomolecular mechanism.
Donald Forsdyke
Yes, the cell has evolved mechanisms (RNA helicases and other RNA-binding proteins) to overcome what appears at the mRNA level as superfluous structure. However, it is not true to state that "there is nothing about their sequence which selects against structure." A sequence as it appears today represents an evolutionary compromise between selective demands such as (a) for DNA structure, (b) for RNA structure, (c) for amino acid sequence ('protein pressure'), (d) for a particular base composition ('GC-pressure'), and (e) for excess purines in exons ('purine-loading pressure') (1).
For example, a triplet AAA encoding lysine might be best for protein function, but might conflict with structural needs at the nucleic acid level, or the need for a high genomic GC value. The evolutionary compromise might be to use the triplet AAG that also codes for lysine, or switch to another basic amino acid (arginine). The latter might not best serve the needs of the protein, but does permit more ample satisfaction of other needs (2).
1. Forsdyke, D. R. Evolutionary Bioinformatics, 2nd edition (Springer, New York, 2011).
2. Forsdyke, D. R. Microbes Infect. 16, 96-103 (2014).