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 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.

scholarly journals Base pair conformation-dependent excision of benzo[a]pyrene diol epoxide-guanine adducts by human nucleotide excision repair enzymes.

1997 ◽  
Vol 17 (12) ◽  
pp. 7069-7076 ◽  
Author(s):  
M T Hess ◽  
D Gunz ◽  
N Luneva ◽  
N E Geacintov ◽  
H Naegeli
Keyword(s):  
Nucleotide Excision Repair ◽  
Dna Adducts ◽  
Excision Repair ◽  
Dna Conformation ◽  
Repair Processes ◽  
Repair Enzymes ◽  
Diol Epoxide ◽  
Nucleotide Excision ◽  
Guanine Adducts ◽  
Repair Activity

Human nucleotide excision repair processes carcinogen-DNA adducts at highly variable rates, even at adjacent sites along individual genes. Here, we identify conformational determinants of fast or slow repair by testing excision of N2-guanine adducts formed by benzo[a]pyrene diol epoxide (BPDE), a potent and ubiquitous mutagen that induces mainly G x C-->T x A transversions and frameshift deletions. We found that human nucleotide excision repair processes the predominant (+)-trans-BPDE-N2-dG adduct 15 times less efficiently than a standard acetylaminofluorene-C8-dG lesion in the same sequence. No difference was observed between (+)-trans- and (-)-trans-BPDE-N2-dG, but excision was enhanced about 10-fold by changing the adduct configurations to either (+)-cis- or (-)-cis-BPDE-N2-dG. Conversely, excision of (+)-cis- and (-)-cis- but not (+)-trans-BPDE-N2-dG was reduced about 10-fold when the complementary cytosine was replaced by adenine, and excision of these BPDE lesions was essentially abolished when the complementary deoxyribonucleotide was missing. Thus, a set of chemically identical BPDE adducts yielded a greater-than-100-fold range of repair rates, demonstrating that nucleotide excision repair activity is entirely dictated by local DNA conformation. In particular, this unique comparison between structurally highly defined substrates shows that fast excision of BPDE-N2-dG lesions is correlated with displacement of both the modified guanine and its partner base in the complementary strand from their normal intrahelical positions. The very slow excision of carcinogen-DNA adducts located opposite deletion sites reveals a cellular strategy that minimizes the fixation of frameshifts after mutagenic translesion synthesis.

scholarly journals The Sequence Dependence of Human Nucleotide Excision Repair Efficiencies of Benzo[a]pyrene-derived DNA Lesions: Insights into the Structural Factors that Favor Dual Incisions

2009 ◽  
Vol 386 (5) ◽  
pp. 1193-1203 ◽  
Author(s):  
Konstantin Kropachev ◽  
Marina Kolbanovskii ◽  
Yuqin Cai ◽  
Fabian Rodríguez ◽  
Alexander Kolbanovskii ◽  
...  
Keyword(s):  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Dna Lesions ◽  
Structural Factors ◽  
Sequence Dependence ◽  
Nucleotide Excision

scholarly journals Lack of recognition by global-genome nucleotide excision repair accounts for the high mutagenicity and persistence of aristolactam-DNA adducts

2011 ◽  
Vol 40 (6) ◽  
pp. 2494-2505 ◽  
Author(s):  
Victoria S. Sidorenko ◽  
Jung-Eun Yeo ◽  
Radha R. Bonala ◽  
Francis Johnson ◽  
Orlando D. Schärer ◽  
...  
Keyword(s):  
Nucleotide Excision Repair ◽  
Dna Adducts ◽  
Excision Repair ◽  
Nucleotide Excision
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