Oxidatively generated guanine(C8)-Thymine(N3) intrastrand cross-links in double-stranded DNA are repaired by base excision repair pathways

Ibtissam Talhaoui, Vladimir Shafirovich, Zhi Liu, Christine Saint-Pierre, Zhiger Akishev, Bakhyt T. Matkarimov, Didier Gasparutto, Nicholas E. Geacintov, Murat Saparbaev

Research output: Contribution to journalArticle

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Abstract

Oxidatively generated guanine radical cations in DNA can undergo various nucleophilic reactions including the formation of C8-guanine cross-links with adjacent or nearby N3-thymines in DNA in the presence of O2. The G[C8-N3]T lesions have been identified in the DNA of human cells exposed to oxidative stress, and are most likely genotoxic if not removed by cellular defense mechanisms. It has been shown that the G[C8-N3]T lesions are substrates of nucleotide excision repair in human cell extracts. Cleavage at the sites of the lesions was also observed but not further investigated (Ding et al. (2012) Nucleic Acids Res. 40, 2506-2517). Using a panel of eukaryotic and prokaryotic bifunctional DNA glycosylases/lyases (NEIL1, Nei, Fpg, Nth, and NTH1) and apurinic/apyrimidinic (AP) endonucleases (Apn1, APE1, and Nfo), the analysis of cleavage fragments by PAGE and MALDI-TOF/MS show that the G[C8-N3]T lesions in 17-mer duplexes are incised on either side of G, that none of the recovered cleavage fragments contain G, and that T is converted to a normal T in the 3′-fragment cleavage products. The abilities of the DNA glycosylases to incise the DNA strand adjacent to G, while this base is initially cross-linked with T, is a surprising observation and an indication of the versatility of these base excision repair proteins.

Original languageEnglish
Pages (from-to)14610-14617
Number of pages8
JournalJournal of Biological Chemistry
Volume290
Issue number23
DOIs
Publication statusPublished - Jun 5 2015

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Thymine
Guanine
DNA Repair
Repair
DNA Glycosylases
DNA
Cells
DNA-(Apurinic or Apyrimidinic Site) Lyase
Lyases
Oxidative stress
Endonucleases
Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry
Cell Extracts
Nucleic Acids
Cations
Oxidative Stress
Nucleotides
Observation
Substrates
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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Oxidatively generated guanine(C8)-Thymine(N3) intrastrand cross-links in double-stranded DNA are repaired by base excision repair pathways. / Talhaoui, Ibtissam; Shafirovich, Vladimir; Liu, Zhi; Saint-Pierre, Christine; Akishev, Zhiger; Matkarimov, Bakhyt T.; Gasparutto, Didier; Geacintov, Nicholas E.; Saparbaev, Murat.

In: Journal of Biological Chemistry, Vol. 290, No. 23, 05.06.2015, p. 14610-14617.

Research output: Contribution to journalArticle

Talhaoui, I, Shafirovich, V, Liu, Z, Saint-Pierre, C, Akishev, Z, Matkarimov, BT, Gasparutto, D, Geacintov, NE & Saparbaev, M 2015, 'Oxidatively generated guanine(C8)-Thymine(N3) intrastrand cross-links in double-stranded DNA are repaired by base excision repair pathways', Journal of Biological Chemistry, vol. 290, no. 23, pp. 14610-14617. https://doi.org/10.1074/jbc.M115.647487
Talhaoui, Ibtissam ; Shafirovich, Vladimir ; Liu, Zhi ; Saint-Pierre, Christine ; Akishev, Zhiger ; Matkarimov, Bakhyt T. ; Gasparutto, Didier ; Geacintov, Nicholas E. ; Saparbaev, Murat. / Oxidatively generated guanine(C8)-Thymine(N3) intrastrand cross-links in double-stranded DNA are repaired by base excision repair pathways. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 23. pp. 14610-14617.
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abstract = "Oxidatively generated guanine radical cations in DNA can undergo various nucleophilic reactions including the formation of C8-guanine cross-links with adjacent or nearby N3-thymines in DNA in the presence of O2. The G∗[C8-N3]T∗ lesions have been identified in the DNA of human cells exposed to oxidative stress, and are most likely genotoxic if not removed by cellular defense mechanisms. It has been shown that the G∗[C8-N3]T∗ lesions are substrates of nucleotide excision repair in human cell extracts. Cleavage at the sites of the lesions was also observed but not further investigated (Ding et al. (2012) Nucleic Acids Res. 40, 2506-2517). Using a panel of eukaryotic and prokaryotic bifunctional DNA glycosylases/lyases (NEIL1, Nei, Fpg, Nth, and NTH1) and apurinic/apyrimidinic (AP) endonucleases (Apn1, APE1, and Nfo), the analysis of cleavage fragments by PAGE and MALDI-TOF/MS show that the G∗[C8-N3]T∗ lesions in 17-mer duplexes are incised on either side of G∗, that none of the recovered cleavage fragments contain G∗, and that T∗ is converted to a normal T in the 3′-fragment cleavage products. The abilities of the DNA glycosylases to incise the DNA strand adjacent to G∗, while this base is initially cross-linked with T∗, is a surprising observation and an indication of the versatility of these base excision repair proteins.",
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AU - Talhaoui, Ibtissam

AU - Shafirovich, Vladimir

AU - Liu, Zhi

AU - Saint-Pierre, Christine

AU - Akishev, Zhiger

AU - Matkarimov, Bakhyt T.

AU - Gasparutto, Didier

AU - Geacintov, Nicholas E.

AU - Saparbaev, Murat

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N2 - Oxidatively generated guanine radical cations in DNA can undergo various nucleophilic reactions including the formation of C8-guanine cross-links with adjacent or nearby N3-thymines in DNA in the presence of O2. The G∗[C8-N3]T∗ lesions have been identified in the DNA of human cells exposed to oxidative stress, and are most likely genotoxic if not removed by cellular defense mechanisms. It has been shown that the G∗[C8-N3]T∗ lesions are substrates of nucleotide excision repair in human cell extracts. Cleavage at the sites of the lesions was also observed but not further investigated (Ding et al. (2012) Nucleic Acids Res. 40, 2506-2517). Using a panel of eukaryotic and prokaryotic bifunctional DNA glycosylases/lyases (NEIL1, Nei, Fpg, Nth, and NTH1) and apurinic/apyrimidinic (AP) endonucleases (Apn1, APE1, and Nfo), the analysis of cleavage fragments by PAGE and MALDI-TOF/MS show that the G∗[C8-N3]T∗ lesions in 17-mer duplexes are incised on either side of G∗, that none of the recovered cleavage fragments contain G∗, and that T∗ is converted to a normal T in the 3′-fragment cleavage products. The abilities of the DNA glycosylases to incise the DNA strand adjacent to G∗, while this base is initially cross-linked with T∗, is a surprising observation and an indication of the versatility of these base excision repair proteins.

AB - Oxidatively generated guanine radical cations in DNA can undergo various nucleophilic reactions including the formation of C8-guanine cross-links with adjacent or nearby N3-thymines in DNA in the presence of O2. The G∗[C8-N3]T∗ lesions have been identified in the DNA of human cells exposed to oxidative stress, and are most likely genotoxic if not removed by cellular defense mechanisms. It has been shown that the G∗[C8-N3]T∗ lesions are substrates of nucleotide excision repair in human cell extracts. Cleavage at the sites of the lesions was also observed but not further investigated (Ding et al. (2012) Nucleic Acids Res. 40, 2506-2517). Using a panel of eukaryotic and prokaryotic bifunctional DNA glycosylases/lyases (NEIL1, Nei, Fpg, Nth, and NTH1) and apurinic/apyrimidinic (AP) endonucleases (Apn1, APE1, and Nfo), the analysis of cleavage fragments by PAGE and MALDI-TOF/MS show that the G∗[C8-N3]T∗ lesions in 17-mer duplexes are incised on either side of G∗, that none of the recovered cleavage fragments contain G∗, and that T∗ is converted to a normal T in the 3′-fragment cleavage products. The abilities of the DNA glycosylases to incise the DNA strand adjacent to G∗, while this base is initially cross-linked with T∗, is a surprising observation and an indication of the versatility of these base excision repair proteins.

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