Structural, energetic and dynamic properties of guanine(C8)-thymine(N3) cross-links in DNA provide insights on susceptibility to nucleotide excision repair

Shuang Ding, Konstantin Kropachev, Yuqin Cai, Marina Kolbanovskiy, Svetlana A. Durandina, Zhi Liu, Vladimir Shafirovich, Suse Broyde, Nicholas E. Geacintov

Research output: Contribution to journalArticle

Abstract

The one-electron oxidation of guanine in DNA by carbonate radical anions, a decomposition product of peroxynitrosocarbonate which is associated with the inflammatory response, can lead to the formation of intrastrand cross-links between guanine and thymine bases [Crean et al. (Oxidation of single-stranded oligonucleotides by carbonate radical anions: generating intrastrand cross-links between guanine and thymine bases separated by cytosines. Nucleic Acids Res. 2008; 36: 742-755.)]. These involve covalent bonds between the C8 positions of guanine (G*) and N3 of thymine (T *) in 5′-d(.G *pT *.) and 5′-d(.G *pCpT *.) sequence contexts. We have performed nucleotide excision repair (NER) experiments in human HeLa cell extracts which show that the G *CT * intrastrand cross-link is excised with approximately four times greater efficiency than the G *T * cross-link embedded in 135-mer DNA duplexes. In addition, thermal melting studies reveal that both lesions significantly destabilize duplex DNA, and that the destabilization induced by the G *CT * cross-link is considerably greater. Consistent with this difference in NER, our computations show that both lesions dynamically distort and destabilize duplex DNA. They disturb Watson-Crick base-pairing and base-stacking interactions, and cause untwisting and minor groove opening. These structural perturbations are much more pronounced in the G *CT * than in the G *T * cross-link. Our combined experimental and computational studies provide structural and thermodynamic understanding of the features of the damaged duplexes that produce the most robust NER response.

Original languageEnglish (US)
Pages (from-to)2506-2517
Number of pages12
JournalNucleic Acids Research
Volume40
Issue number6
DOIs
StatePublished - Mar 2012

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Thymine
Guanine
DNA Repair
Carbonates
DNA
Anions
Cytosine
Cell Extracts
HeLa Cells
Thermodynamics
Oligonucleotides
Base Pairing
Nucleic Acids
Freezing
Hot Temperature
Electrons

ASJC Scopus subject areas

  • Genetics

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Structural, energetic and dynamic properties of guanine(C8)-thymine(N3) cross-links in DNA provide insights on susceptibility to nucleotide excision repair. / Ding, Shuang; Kropachev, Konstantin; Cai, Yuqin; Kolbanovskiy, Marina; Durandina, Svetlana A.; Liu, Zhi; Shafirovich, Vladimir; Broyde, Suse; Geacintov, Nicholas E.

In: Nucleic Acids Research, Vol. 40, No. 6, 03.2012, p. 2506-2517.

Research output: Contribution to journalArticle

Ding, Shuang ; Kropachev, Konstantin ; Cai, Yuqin ; Kolbanovskiy, Marina ; Durandina, Svetlana A. ; Liu, Zhi ; Shafirovich, Vladimir ; Broyde, Suse ; Geacintov, Nicholas E. / Structural, energetic and dynamic properties of guanine(C8)-thymine(N3) cross-links in DNA provide insights on susceptibility to nucleotide excision repair. In: Nucleic Acids Research. 2012 ; Vol. 40, No. 6. pp. 2506-2517.
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AU - Ding, Shuang

AU - Kropachev, Konstantin

AU - Cai, Yuqin

AU - Kolbanovskiy, Marina

AU - Durandina, Svetlana A.

AU - Liu, Zhi

AU - Shafirovich, Vladimir

AU - Broyde, Suse

AU - Geacintov, Nicholas E.

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AB - The one-electron oxidation of guanine in DNA by carbonate radical anions, a decomposition product of peroxynitrosocarbonate which is associated with the inflammatory response, can lead to the formation of intrastrand cross-links between guanine and thymine bases [Crean et al. (Oxidation of single-stranded oligonucleotides by carbonate radical anions: generating intrastrand cross-links between guanine and thymine bases separated by cytosines. Nucleic Acids Res. 2008; 36: 742-755.)]. These involve covalent bonds between the C8 positions of guanine (G*) and N3 of thymine (T *) in 5′-d(.G *pT *.) and 5′-d(.G *pCpT *.) sequence contexts. We have performed nucleotide excision repair (NER) experiments in human HeLa cell extracts which show that the G *CT * intrastrand cross-link is excised with approximately four times greater efficiency than the G *T * cross-link embedded in 135-mer DNA duplexes. In addition, thermal melting studies reveal that both lesions significantly destabilize duplex DNA, and that the destabilization induced by the G *CT * cross-link is considerably greater. Consistent with this difference in NER, our computations show that both lesions dynamically distort and destabilize duplex DNA. They disturb Watson-Crick base-pairing and base-stacking interactions, and cause untwisting and minor groove opening. These structural perturbations are much more pronounced in the G *CT * than in the G *T * cross-link. Our combined experimental and computational studies provide structural and thermodynamic understanding of the features of the damaged duplexes that produce the most robust NER response.

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