scholarly journals Formation, Repair, and Genotoxic Properties of Bulky DNA Adducts Formed from Tobacco-Specific Nitrosamines

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Lisa A. Peterson
Keyword(s):  
Dna Adducts ◽  
Excision Repair ◽  
Laboratory Animals ◽  
Target Tissue ◽  
Abasic Sites ◽  
Nucleotide Excision ◽  
Bulky Dna Adducts ◽  
Repair Pathways ◽  
Tobacco Specific Nitrosamines ◽  
Alkylate Dna

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) andN′-nitrosonornicotine (NNN) are tobacco-specific nitrosamines present in tobacco products and smoke. Both compounds are carcinogenic in laboratory animals, generating tumors at sites comparable to those observed in smokers. These Group 1 human carcinogens are metabolized to reactive intermediates that alkylate DNA. This paper focuses on the DNA pyridyloxobutylation pathway which is common to both compounds. This DNA route generates 7-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxyguanosine,O2-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxycytosine,O2-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxythymidine, andO6-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxyguanosine as well as unstable adducts which dealkylate to release 4-hydroxy-1-{3-pyridyl)-1-butanone or depyriminidate/depurinate to generate abasic sites. There are multiple repair pathways responsible for protecting against the genotoxic effects of these adducts, including adduct reversal as well as base and nucleotide excision repair pathways. Data indicate that several DNA adducts contribute to the overall mutagenic properties of pyridyloxobutylating agents. Which adducts contribute to the carcinogenic properties of this pathway are likely to depend on the biochemistry of the target tissue.

Thermodynamic and structural factors in the removal of bulky DNA adducts by the nucleotide excision repair machinery

Biopolymers ◽  
2002 ◽  
Vol 65 (3) ◽  
pp. 202-210 ◽  
Author(s):  
Nicholas E. Geacintov ◽  
Suse Broyde ◽  
Tonko Buterin ◽  
Hanspeter Naegeli ◽  
Min Wu ◽  
...  
Keyword(s):  
Nucleotide Excision Repair ◽  
Dna Adducts ◽  
Excision Repair ◽  
Structural Factors ◽  
Nucleotide Excision ◽  
Bulky Dna Adducts

scholarly journals Excision of Oxidatively Generated Guanine Lesions by Competitive DNA Repair Pathways

2021 ◽  
Vol 22 (5) ◽  
pp. 2698
Author(s):  
Vladimir Shafirovich ◽  
Nicholas E. Geacintov
Keyword(s):  
Excision Repair ◽  
Dna Lesions ◽  
Dna Templates ◽  
Circular Dna ◽  
Damage Sensing ◽  
Cell Extracts ◽  
Dna Base ◽  
Nucleotide Excision ◽  
Repair Pathways ◽  
Cellular Dna

The base and nucleotide excision repair pathways (BER and NER, respectively) are two major mechanisms that remove DNA lesions formed by the reactions of genotoxic intermediates with cellular DNA. It is generally believed that small non-bulky oxidatively generated DNA base modifications are removed by BER pathways, whereas DNA helix-distorting bulky lesions derived from the attack of chemical carcinogens or UV irradiation are repaired by the NER machinery. However, existing and growing experimental evidence indicates that oxidatively generated DNA lesions can be repaired by competitive BER and NER pathways in human cell extracts and intact human cells. Here, we focus on the interplay and competition of BER and NER pathways in excising oxidatively generated guanine lesions site-specifically positioned in plasmid DNA templates constructed by a gapped-vector technology. These experiments demonstrate a significant enhancement of the NER yields in covalently closed circular DNA plasmids (relative to the same, but linearized form of the same plasmid) harboring certain oxidatively generated guanine lesions. The interplay between the BER and NER pathways that remove oxidatively generated guanine lesions are reviewed and discussed in terms of competitive binding of the BER proteins and the DNA damage-sensing NER factor XPC-RAD23B to these lesions.

scholarly journals Abasic Sites in the Transcribed Strand of Yeast DNA Are Removed by Transcription-Coupled Nucleotide Excision Repair

2010 ◽  
Vol 30 (13) ◽  
pp. 3206-3215 ◽  
Author(s):  
Nayun Kim ◽  
Sue Jinks-Robertson
Keyword(s):  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Genome Integrity ◽  
Genetic Studies ◽  
Abasic Sites ◽  
Dna And Rna ◽  
Nucleotide Excision ◽  
Ap Sites ◽  
Base Excision ◽  
Ap Site

ABSTRACT Abasic (AP) sites are potent blocks to DNA and RNA polymerases, and their repair is essential for maintaining genome integrity. Although AP sites are efficiently dealt with through the base excision repair (BER) pathway, genetic studies suggest that repair also can occur via nucleotide excision repair (NER). The involvement of NER in AP-site removal has been puzzling, however, as this pathway is thought to target only bulky lesions. Here, we examine the repair of AP sites generated when uracil is removed from a highly transcribed gene in yeast. Because uracil is incorporated instead of thymine under these conditions, the position of the resulting AP site is known. Results demonstrate that only AP sites on the transcribed strand are efficient substrates for NER, suggesting the recruitment of the NER machinery by an AP-blocked RNA polymerase. Such transcription-coupled NER of AP sites may explain previously suggested links between the BER pathway and transcription.

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