Aristolochic acids (AA) are associated with AA nephropathy and urothelialcancer. Upon metabolic activation, AA reacts with DNA forming the mutagenicdA-aristolactam (AL) and dG-AL adducts. dA-AL adducts are remarkably persistentin human cells, indicating that they are resistant to repair. Interestingly,mutations in the TP53 gene in humanurothelial cancers induced by AA are limited to non-transcribed strand,suggesting that transcription coupled nucleotide excision repair (NER), but notglobal genome NER efficiently removed dA-AL adducts. We have generated plasmidscontaining a site-specific dA-AL or dG-AL lesion and have studied how theseadducts are repaired by NER. Our studies indicate that the repair efficiencyderived is dependent upon the sequence context in which these lesions are foundand that dA-AL is entirely resistant to repair in certain contexts. Presentstudies are aimed at understanding how these differences are correlated withthe binding of the damage recognition protein XPC-RAD23B.

Sequence-context dependent recognition and repair of aristolochic
acid-DNA adducts

240th National Meeting (2010)

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Sequence-context dependent recognition and repair of aristolochic acid-DNA adducts