Oxidatively Generated Guanine(C8)-Thymine(N3) Intrastrand Cross-links in Double-stranded DNA Are Repaired by Base Excision Repair Pathways

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

doi:10.1074/jbc.m115.647487

Cited by 17 publications

(11 citation statements)

References 45 publications

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“…Such a 5Ј-fragment is not evident in our cell extract experiments ( Fig. 2A) because its mobility would be even slower than that of a fragment with a 3Ј-OH group (70).…”

Section: Ber and Ner Activities Are Observable In The Same Humanmentioning

confidence: 77%

Base and Nucleotide Excision Repair of Oxidatively Generated Guanine Lesions in DNA

Shafirovich

Kropachev

Anderson

et al. 2016

Journal of Biological Chemistry

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The well known biomarker of oxidative stress, 8-oxo-7,8-dihydroguanine, is more susceptible to further oxidation than the parent guanine base and can be oxidatively transformed to the genotoxic spiroiminodihydantoin (Sp) and 5-guanidinohydantoin (Gh) lesions. Incubation of 135-mer duplexes with single Sp or Gh lesions in human cell extracts yields a characteristic nucleotide excision repair (NER)-induced ladder of short dual incision oligonucleotide fragments in addition to base excision repair (BER) incision products. The ladders were not observed when NER was inhibited either by mouse monoclonal antibody (5F12) to human XPA or in XPC ؊/؊ fibroblast cell extracts. The overproduction of free radical intermediates and electrophiles by macrophages and neutrophils activated during the inflammatory response in chronically inflamed tissues induces persistent damage to cellular DNA (1). If not properly repaired, this DNA damage can increase levels of mutations and genomic instability and eventually can lead to the initiation of human cancers (2-4). The primary target of oxidatively generated DNA damage is guanine (5), the most easily oxidizable natural nucleic acid base (6). The best known oxidation product of guanine is 8-oxo-7,8-dihydroguanine (8-oxoG), 3 which is ubiquitous in cellular DNA and is used widely as a biomarker of oxidative stress (7). The 8-oxoG lesion is genotoxic, and failure to remove 8-oxoG before replication induces G:C 3 T:A transversion mutations (8). This lesion is even more easily oxidized than the parent base guanine (9), and its further oxidation by various oxidizing agents, including peroxynitrite, leads to the formation of stereoisomeric spiroiminodihydantoin (Sp) and 5-guanidinohydantoin (Gh) lesions (10 -15). In the case of guanine oxidation by peroxynitrite, the 5-guanidino-4-nitroimidazole (NIm) lesion (16 -18) is also produced and can serve as a biomarker of inflammation-related oxidation mechanisms (1). The NIm lesions together with the easily depurinated 8-nitroguanine, are typical products of guanine damage in calf thymus DNA induced by reactions with nitrosoperoxycarbonate (16, 19) derived from the combination of carbon dioxide and peroxynitrite (20). The structures of these oxidatively generated guanine lesions are shown in Fig. 1A.The chiral carbons in the Gh and Sp nucleobases give rise to a pair of R and S diastereomers. Oligonucleotides that contain single, site-specifically inserted Gh or Sp lesions can be separated and purified by anion-exchange HPLC methods (21). In aqueous solutions, the Gh diastereomers are easily interconvertible, and it is, therefore, not feasible to study their characteristics individually (22). In contrast, the Sp-S and Sp-R diastereomers are chemically stable and can be purified and studied individually (10,23). NMR structural studies in solution indicate that both stereoisomerically distinct Sp lesions (24) perturb adjacent base pairs and thus thermodynamically destabilize oligonucleotide duplexes (25). Molecular modeling studies indicate that the ...

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“…Such a 5Ј-fragment is not evident in our cell extract experiments ( Fig. 2A) because its mobility would be even slower than that of a fragment with a 3Ј-OH group (70).…”

Section: Ber and Ner Activities Are Observable In The Same Humanmentioning

confidence: 77%

Base and Nucleotide Excision Repair of Oxidatively Generated Guanine Lesions in DNA

Shafirovich

Kropachev

Anderson

et al. 2016

Journal of Biological Chemistry

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“…258 In vitro studies performed in HeLa cell extracts have demonstrated that the d(G[8- N 3]T) lesions could be potential substrates of both NER and BER pathways. 259,260 Another recent primer extension experiment revealed that the d(G[8- N 3]T) lesions could strongly block the A-family BF polymerase from Bacillus stearothermophilus , Y-family polymerases Dpo4 from Sulfolobus sulfataricus P2 and human Pol κ , with bypass efficiencies being <1–2%, ∼8%, and 9–11%, respectively. 261 In addition, the primer extension catalyzed by Pol η was also partially inhibited (with bypass efficiency being 28–45%) by the d(G[8- N 3]T) cross-links, and more efficient bypass of nonadjacent d(G[8- N 3]T) lesions in the GCT sequence context was observed than the adjacent counterpart in the GT sequence context.…”

Section: Repair and Biological Consequences Of Oxidative Stress-inmentioning

confidence: 99%

Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage

Cui

Niedernhofer

et al. 2016

Chem. Res. Toxicol.

146

135

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A variety of endogenous and exogenous agents can induce DNA damage and lead to genomic instability. Reactive oxygen species (ROS), an important class of DNA damaging agents, are constantly generated in cells as a consequence of endogenous metabolism, infection/inflammation, and/or exposure to environmental toxicants. A wide array of DNA lesions can be induced by ROS directly, including single-nucleobase lesions, tandem lesions, and hypochlorous acid (HOCl)/hypobromous acid (HOBr)-derived DNA adducts. ROS can also lead to lipid peroxidation, whose byproducts can also react with DNA to produce exocyclic DNA lesions. A combination of bioanalytical chemistry, synthetic organic chemistry, and molecular biology approaches have provided significant insights into the occurrence, repair, and biological consequences of oxidatively induced DNA lesions. The involvement of these lesions in the etiology of human diseases and aging was also investigated in the past several decades, suggesting that the oxidatively induced DNA adducts, especially bulky DNA lesions, may serve as biomarkers for exploring the role of oxidative stress in human diseases. The continuing development and improvement of LC-MS/MS coupled with the stable isotope-dilution method for DNA adduct quantification will further promote research about the clinical implications and diagnostic applications of oxidatively induced DNA adducts.

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“…In contrast to 5′,8-cyclopurine lesions, the G*CT* and G*T* IntraCL lesions are incised in human HeLa cell extracts by BER as well as by NER mechanisms [101]. Detailed studies with purified repair proteins have shown that the bacterial, yeast, and human bifunctional DNA glycosylases (Nei, NEIL1, Nth, NTH1), as well as AP endonucleases (Nfo, Apn1 and APE1) cleave the strands adjacent to the G*CT* and G*T* IntraCL lesions (Fig.…”

Section: Interplay Between Ber and Ner Pathways In The Repair Of Omentioning

confidence: 99%

“…3), in combination with MALDI-TOF/MS methods, showed that the DNA glycosylases/AP lyases excise the cross-linked guanine and cleave the resulting abasic sites via β- and β,δ-elimination mechanisms. In turn, the AP endonucleases of E. coli, Nfo, yeast Apn1 and human APE1 cleave the duplex DNA containing G*CT* and G*T* lesions on the 5′-side of the cross-linked guanine, and are thus capable of initiating the nucleotide incision repair pathway [101]. These experiments were performed with purified proteins in vitro and clearly show that the G*T* and G*CT* intrastrand crosslinks are efficiently incised by BER and NIR pathways at the sites of these lesions.…”

Section: Interplay Between Ber and Ner Pathways In The Repair Of Omentioning

confidence: 99%

Removal of oxidatively generated DNA damage by overlapping repair pathways

Shafirovich

Geacintov

2017

Free Radical Biology and Medicine

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It is generally believed that the mammalian nucleotide excision repair pathway removes DNA helix-distorting bulky DNA lesions, while small non-bulky lesions are repaired by base excision repair (BER). However, recent work demonstrates that the oxidativly generated guanine oxidation products, spiroimininodihydantoin (Sp), 5-guanidinohydantoin (Gh), and certain intrastrand cross-linked lesions, are good substrates of NER and BER pathways that compete with one another in human cell extracts. The oxidation of guanine by peroxynitrite is known to generate 5-guanidino-4-nitroimidazole (NIm) which is structurally similar to Gh, except that the 4-nitro group in NIm is replaced by a keto group in Gh. However, unlike Gh, NIm is an excellent substrate of BER, but not of NER. These and other related results are reviewed and discussed in this article.

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Oxidatively Generated Guanine(C8)-Thymine(N3) Intrastrand Cross-links in Double-stranded DNA Are Repaired by Base Excision Repair Pathways

Cited by 17 publications

References 45 publications

Base and Nucleotide Excision Repair of Oxidatively Generated Guanine Lesions in DNA

Base and Nucleotide Excision Repair of Oxidatively Generated Guanine Lesions in DNA

Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage

Removal of oxidatively generated DNA damage by overlapping repair pathways

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