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PMID: 10573122 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Relationship between internucleotide linkage geometry and the stability of RNA.

RNA (New York, N.Y.) ·Vol. 5 ·No. 10 ·1999-10-00 ·Pages 1308-25

Soukup GA, Breaker RR

Abstract

The inherent chemical instability of RNA under physiological conditions is primarily due to the spontaneous cleavage of phosphodiester linkages via intramolecular transesterification reactions. Although the protonation state of the nucleophilic 2'-hydroxyl group is a critical determinant of the rate of RNA cleavage, the precise geometry of the chemical groups that comprise each internucleotide linkage also has a significant impact on cleavage activity. Specifically, transesterification is expected to be proportional to the relative in-line character of the linkage. We have examined the rates of spontaneous cleavage of various RNAs for which the secondary and tertiary structures have previously been modeled using either NMR or X-ray crystallographic data. Rate constants determined for the spontaneous cleavage of different RNA linkages vary by almost 10,000-fold, most likely reflecting the contribution that secondary and tertiary structures make towards the overall chemical stability of RNA. Moreover, a correlation is observed between RNA cleavage rate and the relative in-line fitness of each internucleotide linkage. One linkage located within an ATP-binding RNA aptamer is predicted to adopt most closely the ideal conformation for in-line attack. This linkage has a rate constant for transesterification that is approximately 12-fold greater than is observed for an unconstrained linkage and was found to be the most labile among a total of 136 different sites examined. The implications of this relationship for the chemical stability of RNA and for the mechanisms of nucleases and ribozymes are discussed.

MeSH Terms
Adenosine Triphosphate/metabolism Base Sequence Flavin Mononucleotide/metabolism Hepatitis Delta Virus/genetics,metabolism Models, Molecular Molecular Sequence Data Nucleic Acid Conformation Nucleotides RNA/chemistry,metabolism RNA Stability RNA, Catalytic/chemistry,metabolism RNA, Protozoan/chemistry,metabolism RNA, Viral/chemistry,metabolism
Chemicals
Nucleotides RNA, Catalytic RNA, Protozoan RNA, Viral RNA Flavin Mononucleotide Adenosine Triphosphate
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Soukup G A
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520-8103, USA.
Breaker R R
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Article Info
Journal
RNA (New York, N.Y.)
Abbr.
RNA
ISSN
1355-8382
DOI
10.1017/s1355838299990891
Published
1999-10-00
Pages
1308-25
Language
English
Region
United States
NLM ID
9509184
PMCID
PMC1369853
Subset
IM
External Links
PubMed source DOI: 10.1017/s1355838299990891 PMC Full Text View journal details
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