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Lack of recognition by global-genome nucleotide excision repair accounts for the high mutagenicity and persistence of aristolactam-DNA adducts
- Source :
- Nucleic Acids Research
- Publication Year :
- 2011
-
Abstract
- Exposure to aristolochic acid (AA), a component of Aristolochia plants used in herbal remedies, is associated with chronic kidney disease and urothelial carcinomas of the upper urinary tract. Following metabolic activation, AA reacts with dA and dG residues in DNA to form aristolactam (AL)-DNA adducts. These mutagenic lesions generate a unique TP53 mutation spectrum, dominated by A : T to T : A transversions with mutations at dA residues located almost exclusively on the non-transcribed strand. We determined the level of AL-dA adducts in human fibroblasts treated with AA to determine if this marked strand bias could be accounted for by selective resistance to global-genome nucleotide excision repair (GG-NER). AL-dA adduct levels were elevated in cells deficient in GG-NER and transcription-coupled NER, but not in XPC cell lines lacking GG-NER only. In vitro, plasmids containing a single AL-dA adduct were resistant to the early recognition and incision steps of NER. Additionally, the NER damage sensor, XPC-RAD23B, failed to specifically bind to AL-DNA adducts. However, placing AL-dA in mismatched sequences promotes XPC-RAD23B binding and renders this adduct susceptible to NER, suggesting that specific structural features of this adduct prevent processing by NER. We conclude that AL-dA adducts are not recognized by GG-NER, explaining their high mutagenicity and persistence in target tissues.
- Subjects :
- congenital, hereditary, and neonatal diseases and abnormalities
DNA Repair
DNA repair
Aristolochic acid
Biology
Genome Integrity, Repair and Replication
medicine.disease_cause
Heterocyclic Compounds, 4 or More Rings
Cell Line
03 medical and health sciences
chemistry.chemical_compound
DNA Adducts
0302 clinical medicine
Genetics
medicine
Humans
skin and connective tissue diseases
030304 developmental biology
0303 health sciences
Mutation
Global genome nucleotide-excision repair
Deoxyadenosines
Genome, Human
Adenine
Mutagenesis
nutritional and metabolic diseases
Molecular biology
3. Good health
DNA-Binding Proteins
chemistry
Biochemistry
Adductomics
030220 oncology & carcinogenesis
Aristolochic Acids
DNA
Nucleotide excision repair
Mutagens
Subjects
Details
- ISSN :
- 13624962
- Volume :
- 40
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Nucleic acids research
- Accession number :
- edsair.doi.dedup.....0a4d3c9b662d6d209398f591f0e90e5c