The reactivity of phosphodiester bonds within linear single-stranded oligoribonucleotides is strongly dependent on the base sequence

Kaukinen, U.

doi:10.1093/nar/30.2.468

Cited by 69DNA and Nucleic Acid ChemistryChemical Reaction MechanismsRNA and protein synthesis mechanisms

The reactivity of phosphodiester bonds within linear single-stranded oligoribonucleotides is strongly dependent on the base sequence

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Kaukinen, U.·2002·Nucleic Acids Research

DOI 10.1093/nar/30.2.468PMC PMC99829

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Abstract

The cleavage of short chimeric oligonucleotides containing only one reactive ribonucleoside unit, all other nucleosides being 2'-O-methylated, has been studied at pH 8.5 and 35 degrees C. Among the 20 different sequences that did not exhibit any tendency to form a defined secondary structure, the scissile 5'-UpA-3' and 5'-CpA-3' phosphodiester bonds experienced >100- and up to 35-fold reactivity differences, respectively. Compared with dinucleoside monophosphates, both rate accelerations and retardations of more than one order of magnitude were observed. Even a change of a single base several nucleosides away from the scissile bond markedly affected the reaction rate. Duplex formation at the 3'- and/or 5'-side of the scissile bond was also studied and observed to be strongly rate retarding. The origin of the high sensitivity of phosphodiester bonds to the molecular environment is discussed.

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Independent of the nucleotide identity 5' of the U, the bond leading to 3' U is a hotspot for in-line nucleophilic attack.
“Thus, independent of the nucleotide identity 5’ of the U, this bond is a hotspot for in-line nucleophilic attack63,65.”
From Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics (2022) · cites this paper as [63]
The Results (page unavailable) report that cleavage of the studied 5′-UpA-3′ bond varies strongly with the surrounding sequence; in one sequence, no reaction was detected in three months. The Discussion (page unavailable) explicitly rejects the idea that this bond is inherently prone to cleavage. The paper studies a bond following U, rather than establishing that a bond leading to 3′ U is a hotspot independent of the preceding nucleotide. (LLM, conf=0.82)
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The base sequence and secondary structure of mRNA influence the rate of hydrolysis.
“In two publications on mRNA hydrolysis the authors state that the base sequence and secondary structure of mRNA influence the rate of hydrolysis (Kaukinen et al., 2002, Mikkola et al., 2001).”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Kaukinen et al., 2002
Base-stacking may decrease the cleavage rate of phosphodiester bonds.
“Specifically, base-stacking may decrease the cleavage rate of phosphodiester bonds.”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Kaukinen et al., 2002

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Authors: Kaukinen, U.
Affiliations: University of Turku (FI)
Corresponding author: Kaukinen, U.
Venue: Nucleic Acids Research
Publisher: Oxford University Press (OUP)
Published: 2002-01-15
Volume: 30
Issue: 2
Pages: 468-474
ISSN: 0305-1048 (ISSN-L)
1362-4962
DOI: 10.1093/nar/30.2.468
PMC: PMC99829
OpenAlex: W2040448004
Cited by: 69
References: 45
Citations by year: 2026: 6 · 2025: 1 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 5 · 2014: 1 · 2013: 1
FWCI: 1.97
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Nucleic Acids Research (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords: base sequence dependence, chimeric oligonucleotides, dinucleoside monophosphates, duplex formation, molecular environment effects, nucleophilic cleavage
MeSH terms: Base Composition, Base Sequence, Kinetics, Nucleic Acid Conformation, Nucleic Acid Denaturation, Oligoribonucleotides, Temperature

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The reactivity of phosphodiester bonds within linear single-stranded oligoribonucleotides is strongly dependent on the base sequence

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