Limits...
Novel RNA base pair with higher specificity using single selenium atom.

Sun H, Sheng J, Hassan AE, Jiang S, Gan J, Huang Z - Nucleic Acids Res. (2012)

Bottom Line: Specificity of nucleobase pairing provides essential foundation for genetic information storage, replication, transcription and translation in all living organisms.In order to increase U/A pairing specificity, we have hypothesized to discriminate against U/G wobble pair by tailoring the steric and electronic effects at the 2-exo position of uridine and replacing the 2-exo oxygen with a selenium atom.We reveal that the (Se)U/A pair maintains a structure virtually identical to the native U/A base pair, while discriminating against U/G wobble pair.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.

ABSTRACT
Specificity of nucleobase pairing provides essential foundation for genetic information storage, replication, transcription and translation in all living organisms. However, the wobble base pairs, where U in RNA (or T in DNA) pairs with G instead of A, might compromise the high specificity of the base pairing. The U/G wobble pairing is ubiquitous in RNA, especially in non-coding RNA. In order to increase U/A pairing specificity, we have hypothesized to discriminate against U/G wobble pair by tailoring the steric and electronic effects at the 2-exo position of uridine and replacing the 2-exo oxygen with a selenium atom. We report here the first synthesis of the 2-Se-U-RNAs as well as the 2-Se-uridine ((Se)U) phosphoramidite. Our biophysical and structural studies of the (Se)U-RNAs indicate that this single atom replacement can indeed create a novel U/A base pair with higher specificity than the natural one. We reveal that the (Se)U/A pair maintains a structure virtually identical to the native U/A base pair, while discriminating against U/G wobble pair. This oxygen replacement with selenium offers a unique chemical strategy to enhance the base pairing specificity at the atomic level.

Show MeSH
Native and Se-modified U/A pairs and U/G wobble pairs.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3367167&req=5

gks010-F1: Native and Se-modified U/A pairs and U/G wobble pairs.

Mentions: DNA and RNA are crucial genetic information carriers (1,2). The base pairs of DNAs (T/A and C/G) and RNAs (U/A and C/G) need to be highly specific and accurate for the purpose of the precise genetic information storage, replication, transcription and translation. However, the wobble base pairs, where U in RNA (or T in DNA) pairs with G instead of A, may compromise the high specificity of the base pairing. In RNA, especially non-coding RNA, U/G wobble pair (Figure 1) is ubiquitous (3) and sometimes it has the similar stability as the Watson–Crick U/A pair (4,5). U/G wobble pair offers unique structural and thermodynamic features (3–5). On the one hand, the U/G pairing increases structure and function diversities of RNA (6). But on the other hand, it may jeopardize the pairing specificity and can cause potential mutations in RNA transcription and protein translation. Codon–anticodon mismatch or misreading is observed with an error frequency at 10−5 or higher, which may affect the accuracy of synthesized proteins (7–9). For instance, the first position of the codon–anticodon interaction with wobble mismatch (U/G) was discovered in Escherichia coli (error frequency = 0.1%) with 100-fold higher than the normal error level (9). In this mis-incorporation of serine (codon: AGC) (9), glycine codon (GGC) in mRNA is recognized by Ser-charged tRNA (anticodon: GCU) instead of Gly-charged tRNA (anticodon: GCC). Similarly, the second position of the codon–anticodon interaction with wobble mismatch (U/G) was also observed, where Lys (codon: AAA) is mis-incorporated instead of normal incorporation of Arg (codon: AGA), with much higher error frequency (5–12%) (10). To avoid the negative impact of the wobble pairing on the level of protein synthesis, the genetic codes with degeneracy are used to deal with the consequence of the wobble pairing. Thus, wobble pairing is often observed at the third codon position through the codon degeneracy to limit errors. However, the codons forming the Watson–Crick pairs with tRNA anticodons are still preferred (11,12). Study shows that the third codon position with a Watson–Crick base pair can reduce the frequency of amino acid mis-incorporation by nearly 10-fold, and it is much more accurate than that with a wobble pair for the same amino acid (13). Nevertheless, the 3-nt genetic codes that accommodate the wobble pairing are used as the most ideal countermeasure at the level of protein synthesis in living organisms (14). Clearly, on the basis of the chemical principle, this degeneracy strategy properly guarantees the translation accuracy at the protein level by tolerating wobble pairs and silent mutations at the RNA and DNA levels.Figure 1.


Novel RNA base pair with higher specificity using single selenium atom.

Sun H, Sheng J, Hassan AE, Jiang S, Gan J, Huang Z - Nucleic Acids Res. (2012)

Native and Se-modified U/A pairs and U/G wobble pairs.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3367167&req=5

gks010-F1: Native and Se-modified U/A pairs and U/G wobble pairs.
Mentions: DNA and RNA are crucial genetic information carriers (1,2). The base pairs of DNAs (T/A and C/G) and RNAs (U/A and C/G) need to be highly specific and accurate for the purpose of the precise genetic information storage, replication, transcription and translation. However, the wobble base pairs, where U in RNA (or T in DNA) pairs with G instead of A, may compromise the high specificity of the base pairing. In RNA, especially non-coding RNA, U/G wobble pair (Figure 1) is ubiquitous (3) and sometimes it has the similar stability as the Watson–Crick U/A pair (4,5). U/G wobble pair offers unique structural and thermodynamic features (3–5). On the one hand, the U/G pairing increases structure and function diversities of RNA (6). But on the other hand, it may jeopardize the pairing specificity and can cause potential mutations in RNA transcription and protein translation. Codon–anticodon mismatch or misreading is observed with an error frequency at 10−5 or higher, which may affect the accuracy of synthesized proteins (7–9). For instance, the first position of the codon–anticodon interaction with wobble mismatch (U/G) was discovered in Escherichia coli (error frequency = 0.1%) with 100-fold higher than the normal error level (9). In this mis-incorporation of serine (codon: AGC) (9), glycine codon (GGC) in mRNA is recognized by Ser-charged tRNA (anticodon: GCU) instead of Gly-charged tRNA (anticodon: GCC). Similarly, the second position of the codon–anticodon interaction with wobble mismatch (U/G) was also observed, where Lys (codon: AAA) is mis-incorporated instead of normal incorporation of Arg (codon: AGA), with much higher error frequency (5–12%) (10). To avoid the negative impact of the wobble pairing on the level of protein synthesis, the genetic codes with degeneracy are used to deal with the consequence of the wobble pairing. Thus, wobble pairing is often observed at the third codon position through the codon degeneracy to limit errors. However, the codons forming the Watson–Crick pairs with tRNA anticodons are still preferred (11,12). Study shows that the third codon position with a Watson–Crick base pair can reduce the frequency of amino acid mis-incorporation by nearly 10-fold, and it is much more accurate than that with a wobble pair for the same amino acid (13). Nevertheless, the 3-nt genetic codes that accommodate the wobble pairing are used as the most ideal countermeasure at the level of protein synthesis in living organisms (14). Clearly, on the basis of the chemical principle, this degeneracy strategy properly guarantees the translation accuracy at the protein level by tolerating wobble pairs and silent mutations at the RNA and DNA levels.Figure 1.

Bottom Line: Specificity of nucleobase pairing provides essential foundation for genetic information storage, replication, transcription and translation in all living organisms.In order to increase U/A pairing specificity, we have hypothesized to discriminate against U/G wobble pair by tailoring the steric and electronic effects at the 2-exo position of uridine and replacing the 2-exo oxygen with a selenium atom.We reveal that the (Se)U/A pair maintains a structure virtually identical to the native U/A base pair, while discriminating against U/G wobble pair.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.

ABSTRACT
Specificity of nucleobase pairing provides essential foundation for genetic information storage, replication, transcription and translation in all living organisms. However, the wobble base pairs, where U in RNA (or T in DNA) pairs with G instead of A, might compromise the high specificity of the base pairing. The U/G wobble pairing is ubiquitous in RNA, especially in non-coding RNA. In order to increase U/A pairing specificity, we have hypothesized to discriminate against U/G wobble pair by tailoring the steric and electronic effects at the 2-exo position of uridine and replacing the 2-exo oxygen with a selenium atom. We report here the first synthesis of the 2-Se-U-RNAs as well as the 2-Se-uridine ((Se)U) phosphoramidite. Our biophysical and structural studies of the (Se)U-RNAs indicate that this single atom replacement can indeed create a novel U/A base pair with higher specificity than the natural one. We reveal that the (Se)U/A pair maintains a structure virtually identical to the native U/A base pair, while discriminating against U/G wobble pair. This oxygen replacement with selenium offers a unique chemical strategy to enhance the base pairing specificity at the atomic level.

Show MeSH