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

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-st...

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Main Authors: Ding, Shuang, Kropachev, Konstantin, Cai, Yuqin, Kolbanovskiy, Marina, Durandina, Svetlana A., Liu, Zhi, Shafirovich, Vladimir, Broyde, Suse, Geacintov, Nicholas E.
Format: Online
Language:English
Published: Oxford University Press 2012
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315297/
id pubmed-3315297
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spelling pubmed-33152972012-03-30 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. Genome Integrity, Repair and Replication 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. Oxford University Press 2012-03 2011-11-30 /pmc/articles/PMC3315297/ /pubmed/22135299 http://dx.doi.org/10.1093/nar/gkr1087 Text en © The Author(s) 2011. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Ding, Shuang
Kropachev, Konstantin
Cai, Yuqin
Kolbanovskiy, Marina
Durandina, Svetlana A.
Liu, Zhi
Shafirovich, Vladimir
Broyde, Suse
Geacintov, Nicholas E.
spellingShingle 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
author_facet Ding, Shuang
Kropachev, Konstantin
Cai, Yuqin
Kolbanovskiy, Marina
Durandina, Svetlana A.
Liu, Zhi
Shafirovich, Vladimir
Broyde, Suse
Geacintov, Nicholas E.
author_sort Ding, Shuang
title Structural, energetic and dynamic properties of guanine(C8)–thymine(N3) cross-links in DNA provide insights on susceptibility to nucleotide excision repair
title_short Structural, energetic and dynamic properties of guanine(C8)–thymine(N3) cross-links in DNA provide insights on susceptibility to nucleotide excision repair
title_full Structural, energetic and dynamic properties of guanine(C8)–thymine(N3) cross-links in DNA provide insights on susceptibility to nucleotide excision repair
title_fullStr Structural, energetic and dynamic properties of guanine(C8)–thymine(N3) cross-links in DNA provide insights on susceptibility to nucleotide excision repair
title_full_unstemmed Structural, energetic and dynamic properties of guanine(C8)–thymine(N3) cross-links in DNA provide insights on susceptibility to nucleotide excision repair
title_sort structural, energetic and dynamic properties of guanine(c8)–thymine(n3) cross-links in dna provide insights on susceptibility to nucleotide excision repair
description 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.
publisher Oxford University Press
publishDate 2012
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315297/
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