Base Pairing Configuration and Stability of an Oligonucleotide Duplex Containing a 5-chlorouracil-adenine Base Pair

Overview

Journal Biochemistry

Specialty Biochemistry

Date 2009 Jul 22

PMID 19618901

Citations 7

Authors

Jacob A Theruvathu

Cherine H Kim

Daniel K Rogstad

Jonathan W Neidigh

Lawrence C Sowers

Affiliations

Soon will be listed here.

Abstract

Inflammation-mediated reactive molecules can damage DNA by oxidation and chlorination. The biological consequences of this damage are as yet incompletely understood. In this paper, we have constructed oligonucleotides containing 5-chlorouracil (ClU), one of the known inflammation damage products. The thermodynamic stability, base pairing configuration, and duplex conformation of oligonucleotides containing ClU paired opposite adenine have been examined. NMR spectra reveal that the ClU-A base pair adopts a geometry similar to that of the T-A base pair, and the ClU-A base pair-containing duplex adopts a normal B-form conformation. The line width of the imino proton of the ClU residue is substantially greater than that of the corresponding T imino proton; however, this difference is not attributed to a reduced thermal or thermodynamic stability or to an increased level of proton exchange with solvent. While the NMR studies reveal an increased level of chemical exchange for the ClU imino proton of the ClU-A base pair, the ClU residue is not a target for removal by the Escherichia coli mispaired uracil glycosylase, which senses damage-related helix instability. The results of this study are consistent with previous reports indicating that the DNA of replicating cells can tolerate substantial substitution with ClU. The fraudulent, pseudo-Watson-Crick ClU-A base pair is sufficiently stable to avoid glycosylase removal and, therefore, might constitute a persistent form of cellular DNA damage.

Citing Articles

Synthesis and DNA/RNA complementation studies of peptide nucleic acids containing 5-halouracils.

Liu C, Wang J, Xie Y, Chen H Medchemcomm. 2018; 8(2):385-389.

PMID: 30108754 PMC: 6071789. DOI: 10.1039/c6md00536e.

Incorporating uracil and 5-halouracils into short peptide nucleic acids for enhanced recognition of A-U pairs in dsRNAs.

Patil K, Toh D, Yuan Z, Meng Z, Shu Z, Zhang H Nucleic Acids Res. 2018; 46(15):7506-7521.

PMID: 30011039 PMC: 6125629. DOI: 10.1093/nar/gky631.

Comparison of the structural and dynamic effects of 5-methylcytosine and 5-chlorocytosine in a CpG dinucleotide sequence.

Theruvathu J, Yin Y, Pettitt B, Sowers L Biochemistry. 2013; 52(47):8590-8.

PMID: 24147911 PMC: 3985228. DOI: 10.1021/bi400980c.

Structure, stability and function of 5-chlorouracil modified A:U and G:U base pairs.

Patra A, Harp J, Pallan P, Zhao L, Abramov M, Herdewijn P Nucleic Acids Res. 2013; 41(4):2689-97.

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Impact of base analogues within a CpG dinucleotide on the binding of DNA by the methyl-binding domain of MeCP2 and methylation by DNMT1.

Lao V, Darwanto A, Sowers L Biochemistry. 2010; 49(47):10228-36.

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