scholarly journals Nucleotide Excision Repair Efficiencies of Bulky Carcinogen–DNA Adducts Are Governed by a Balance between Stabilizing and Destabilizing Interactions

Biochemistry ◽  
2012 ◽  
Vol 51 (7) ◽  
pp. 1486-1499 ◽  
Author(s):  
Yuqin Cai ◽  
Nicholas E. Geacintov ◽  
Suse Broyde
Keyword(s):  
Nucleotide Excision Repair ◽  
Dna Adducts ◽  
Excision Repair ◽  
Nucleotide Excision

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 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

scholarly journals Adenine–DNA Adducts Derived from the Highly Tumorigenic Dibenzo[a,l]pyrene Are Resistant to Nucleotide Excision Repair while Guanine Adducts Are Not

2013 ◽  
Vol 26 (5) ◽  
pp. 783-793 ◽  
Author(s):  
Konstantin Kropachev ◽  
Marina Kolbanovskiy ◽  
Zhi Liu ◽  
Yuqin Cai ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Nucleotide Excision Repair ◽  
Dna Adducts ◽  
Excision Repair ◽  
Nucleotide Excision ◽  
Guanine Adducts

scholarly journals Expression of a Human Cytochrome P450 in Yeast Permits Analysis of Pathways for Response to and Repair of Aflatoxin-Induced DNA Damage

2005 ◽  
Vol 25 (14) ◽  
pp. 5823-5833 ◽  
Author(s):  
Yingying Guo ◽  
Linda L. Breeden ◽  
Helmut Zarbl ◽  
Bradley D. Preston ◽  
David L. Eaton
Keyword(s):  
Dna Damage ◽  
Cytochrome P450 ◽  
Nucleotide Excision Repair ◽  
Dna Adducts ◽  
Excision Repair ◽  
Cell Cycle Checkpoints ◽  
Postreplication Repair ◽  
Nucleotide Excision ◽  
Base Excision ◽  
Aflatoxin B

ABSTRACT Aflatoxin B1 (AFB1) is a human hepatotoxin and hepatocarcinogen produced by the mold Aspergillus flavus. In humans, AFB1 is primarily bioactivated by cytochrome P450 1A2 (CYP1A2) and 3A4 to a genotoxic epoxide that forms N7-guanine DNA adducts. A series of yeast haploid mutants defective in DNA repair and cell cycle checkpoints were transformed with human CYP1A2 to investigate how these DNA adducts are repaired. Cell survival and mutagenesis following aflatoxin B1 treatment was assayed in strains defective in nucleotide excision repair (NER) (rad14), postreplication repair (PRR) (rad6, rad18, mms2, and rad5), homologous recombinational repair (HRR) (rad51 and rad54), base excision repair (BER) (apn1 apn2), nonhomologous end-joining (NHEJ) (yku70), mismatch repair (MMR) (pms1), translesion synthesis (TLS) (rev3), and checkpoints (mec1-1, mec1-1 rad53, rad9, and rad17). Together our data suggest the involvement of homologous recombination and nucleotide excision repair, postreplication repair, and checkpoints in the repair and/or tolerance of AFB1-induced DNA damage in the yeast model. Rev3 appears to mediate AFB1-induced mutagenesis when error-free pathways are compromised. The results further suggest unique roles for Rad5 and abasic endonuclease-dependent DNA intermediates in regulating AFB1-induced mutagenicity.

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