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Review
. 2013 Feb 1;41(4):2073-94.
doi: 10.1093/nar/gks1205. Epub 2013 Jan 4.

Sounds of silence: synonymous nucleotides as a key to biological regulation and complexity

Svetlana A Shabalina  1 , Nikolay A Spiridonov, Anna Kashina
Affiliations
Review

Sounds of silence: synonymous nucleotides as a key to biological regulation and complexity

Svetlana A Shabalina et al. Nucleic Acids Res. .

Abstract

Messenger RNA is a key component of an intricate regulatory network of its own. It accommodates numerous nucleotide signals that overlap protein coding sequences and are responsible for multiple levels of regulation and generation of biological complexity. A wealth of structural and regulatory information, which mRNA carries in addition to the encoded amino acid sequence, raises the question of how these signals and overlapping codes are delineated along non-synonymous and synonymous positions in protein coding regions, especially in eukaryotes. Silent or synonymous codon positions, which do not determine amino acid sequences of the encoded proteins, define mRNA secondary structure and stability and affect the rate of translation, folding and post-translational modifications of nascent polypeptides. The RNA level selection is acting on synonymous sites in both prokaryotes and eukaryotes and is more common than previously thought. Selection pressure on the coding gene regions follows three-nucleotide periodic pattern of nucleotide base-pairing in mRNA, which is imposed by the genetic code. Synonymous positions of the coding regions have a higher level of hybridization potential relative to non-synonymous positions, and are multifunctional in their regulatory and structural roles. Recent experimental evidence and analysis of mRNA structure and interspecies conservation suggest that there is an evolutionary tradeoff between selective pressure acting at the RNA and protein levels. Here we provide a comprehensive overview of the studies that define the role of silent positions in regulating RNA structure and processing that exert downstream effects on proteins and their functions.

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Figures

Figure 1.
Figure 1.
Periodic pattern of nucleotide involvement in secondary structure formation and sequence conservation around the start and the stop codons in human mRNAs. Positions from −30 to −1 correspond to 5′-UTRs and positions from 1 to 60 correspond to CDSs (upper left panel). Positions from −60 to −1 correspond to CDSs and positions from 1 to 30 correspond to 3′-UTRs (upper right panel). Blue, sequence conservation in 6919 orthologous human and mouse mRNAs. Red, base-paired nucleotides in 19 317 human mRNAs. Green, free Gibbs energy of base-pairing in 19 317 human mRNAs. Structural features of the untranslated regions (UTRs) and coding sequences (CDSs) have a major role in the control of mRNA translation. The relaxed secondary structures in UTRs are common for many mRNAs and involved in regulation of initiation (low left panel) and termination (low right panel) of translation. Periodic pattern in the CDS is likely responsible for translation frame monitoring (low center panel). Groups of genes with distinct levels of expression (114) are presented in different colors. This figure is adapted from (10).
Figure 2.
Figure 2.
Differential arginylation of actin isoforms is regulated by a novel degradation mechanism coupled to the translation and folding dynamics in vivo. Top, faster translation and folding of beta-actin protects the Lys18 residue from potential co-translational ubiquitination and degradation on N-terminal arginylation. After emerging from the ribosome, arginylated beta-actin remains relatively stable and incorporates into actin cytoskeleton. Bottom, slower translation and folding of gamma-actin coupled with co-translational arginylation exposes arginylated gamma-actin for ubiquitination and ensures effective removal of 60–80% of arginylated gamma-actin protein. The fraction of arginylated gamma-actin that escapes the co-translational ‘check point’ is still degraded faster, with half-life of only 1 h, so that no arginylated gamma-actin can be detected in vivo. Image courtesy of Dr Fangliang Zhang.
Figure 3.
Figure 3.
The multiple contact model of mRNA–rRNA interactions. Hybridization affinity of 16S rRNA to mRNAs in E. coli. mRNA–rRNA interactions follow ‘the multiple contact model’ and occur due to the formation of multiple duplexes between short complementary sites scattered over the sequences (107,108). (A) mRNA–16S rRNA interactions affect translation efficiency. Efficient translation: rRNA clinger elements (red: located at 3′-end of 16S rRNA; brown: other) interact with the mRNA at complementary sites, which are indicated schematically as orange shapes in 5′-UTRs and blue shapes in CDSs. (B) Translation pausing: rRNA clinger elements located at 3′-end of 16S rRNA interact with mRNA sites located in CDSs. (C) The profile of complementarity of the 3′-end domain of 16S rRNA to the 5′ untranslated regions of mRNAs (30 nucleotides upstream AUG for ∼4200 sequences). The anti-Shine-Dalgarno site (UCACCUCC) is marked by arrow. Other clinger elements in the 3′-end of 16S rRNA: 1 (CCCGGGCCC), 2 (GGGAGUGGU), 3 (UCGGGAGGGC), 4 (UGGGGUGAA), 5 (AGGGGAACCUGCGG). (D) The profile of complementarity of 16S rRNA to the coding regions of mRNAs (∼4200 transcripts). Note significantly higher hybridization affinity of the 3′-end domain of 16S rRNA to UTRs (panel C) relatively to CDSs (panel D). Complementary targets to clinger elements in the 3′-end of 16S rRNA are avoided in the coding regions (107), in good agreement with recently published experimental data on the translation pausing driven by the Shine-Dalgarno-like sequences in the coding region of mRNAs (109). Panels C and D are adapted from 107.
Figure 4.
Figure 4.
mRNA–rRNA intermolecular hybridization affinity. Distribution of complementarity of mouse 18S rRNA to several thousand mRNAs. Peaks represent potential clingers on mouse 18S rRNA. Hybridization affinity of abundant and rare protein kinase transcripts to verified 18S rRNA clinger (right insert box). Predicted secondary structure of verified 18S rRNA clinger (left insert box). This figure is adapted from 14 and 114.
Figure 5.
Figure 5.
Correlation between Ka and Ks for codons with single and double substitutions. Ka and Ks were estimated from sequence alignments of complete kinome (∼600 orthologous human and mouse protein kinase mRNAs, analysed in 46) by PAML program (Yang et al.). Strong correlation between Ka and Ks was found for codons with double substitutions, where synonymous and non-synonymous substitutions occur (green dots). Image courtesy of Dr Aleksey Ogurtsov.
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References

    1. Claverie JM. Gene number. What if there are only 30,000 human genes? Science. 2001;291:1255–1257. - PubMed
    1. Pennisi E. Human genome. A low number wins the GeneSweep Pool. Science. 2003;300:1484. - PubMed
    1. Stein LD. Human genome: end of the beginning. Nature. 2004;431:915–916. - PubMed
    1. Shabalina SA, Spiridonov NA. The mammalian transcriptome and the function of non-coding DNA sequences. Genome Biol. 2004;5:105. - PMC - PubMed
    1. Sultan M, Schulz MH, Richard H, Magen A, Klingenhoff A, Scherf M, Seifert M, Borodina T, Soldatov A, Parkhomchuk D, et al. A global view of gene activity and alternative splicing by deep sequencing of the human transcriptome. Science. 2008;321:956–960. - PubMed

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