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

Sidorenko, Victoria S.; Yeo, Jung-Eun; Bonala, Radha; Johnson, Francis; Schärer, Orlando D.; Grollman, Arthur P.

doi:10.1093/nar/gkr1095

Cited by 96 publications

(126 citation statements)

References 56 publications

(79 reference statements)

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“…Its metabolized derivative forms mutagenic aristolactam (AL)-DNA adducts. AL-dA adducts are refractory to the global genome branch of NER (GGR) and can be repaired only by TCR in the transcribed strand 117 , which can explain a transcriptional strand bias and high frequency of A:T→TA mutations in cancer genes such as TP53 118, 119 . The mutation load in upper tract urothelial cancers induced by AA is one of the highest known so far.…”

Section: Hypermutation By Increase In Lesions or By Decrease In Errormentioning

confidence: 99%

Hypermutation in human cancer genomes: footprints and mechanisms

2014

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Preface A role for somatic mutations in carcinogenesis is well accepted, but the degree to which mutation rates influence cancer initiation and development is under continuous debate. Recently accumulated genomic data has revealed that thousands of tumour samples are riddled by hypermutation, broadening support that cancers acquire a mutator phenotype. This major expansion of cancer mutation data sets has provided unprecedented statistical power for the analysis of mutation spectra, which has confirmed several classical sources of mutation in cancer, highlighted new prominent mutation sources and empowered the search for cancer drivers. The confluence of cancer mutation genomics and mechanistic insight provides great promise for understanding the basic development of cancer through mutations.

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Section: Hypermutation By Increase In Lesions or By Decrease In Errormentioning

confidence: 99%

Hypermutation in human cancer genomes: footprints and mechanisms

2014

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“…As with most bulky adducts, dA-AL adducts normally would be excised by global genomic nucleotide excision repair. However, the structure of dA-AL in adducted DNA (28) precludes recognition by XPC/ R23B, the initial step in global genomic repair, while transcription-coupled repair of this lesion is unaffected (29). As a result, dA-AL adducts persist in human tissues for many years (3,6,7).…”

Section: Discussionmentioning

confidence: 99%

Aristolochic acid-associated urothelial cancer in Taiwan

Chen

Dickman

Moriya³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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352

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Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53 mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of 5′ AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.upper urinary tract carcinoma | traditional Chinese medicine | transitional cell carcinoma | DNA damage | herbal medicine

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“…Among the 27,000 mutations in the IARC TP53 database, A-to-T TP53 mutations are found in 5.3% of all human cancers and only 1.4% of UTUCs overall. 13,41 AL-DNA adducts are strongly resistant to global genomic nucleotide excision repair, 42 which accounts for the strand bias in TP53 mutations. The documented exposure to AA through detection of AL-DNA adducts combined with the high number of signature A-to-T mutations on the non-transcribed DNA strand implicate AA as the causative agent in UTUC in the Balkans and Taiwan.…”

Section: Metabolic Activation Dna Adduct Formation and Tp53 Mutatiomentioning

confidence: 99%

New approaches for biomonitoring exposure to the human carcinogen aristolochic acid

et al. 2015

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Aristolochic acids (AA) are found in all Aristolochia herbaceous plants, many of which have been used worldwide for medicinal purposes for centuries. AA are causal agents of the chronic kidney disease entity termed aristolochic acid nephropathy (AAN) and potent upper urinary tract carcinogens in humans. AAN and upper urinary tract cancers are endemic in rural areas of Croatia and other Balkan countries where exposure to AA occurs through the ingestion of home-baked bread contaminated with Aristolochia seeds. In Asia, exposure to AA occurs through usage of traditional Chinese medicinal herbs containing Aristolochia. Despite warnings from regulatory agencies, traditional Chinese herbs containing AA continue to be used world-wide. In this review, we highlight novel approaches to quantify exposure to AA, by analysis of aristolactam (AL) DNA adducts, employing ultraperformance liquid chromatography–electrospray ionization/multistage mass spectrometry (UPLC-ESI/MSn). DNA adducts are a measure of internal exposure to AA and serve as an important end point for cross-species extrapolation of toxicity data and human risk assessment. The level of sensitivity of UPLC-ESI/MSn surpasses the limits of detection of AL-DNA adducts obtained by 32P-postlabeling techniques, the most widely employed methods for detecting putative DNA adducts in humans. AL-DNA adducts can be measured by UPLC-ESI/MS3, not only in fresh frozen renal tissue, but also in formalin-fixed, paraffin-embedded (FFPE) samples, an underutilized biospecimen for assessing chemical exposures, and in exfoliated urinary cells, a non-invasive approach. The frequent detection of AL DNA adducts in renal tissues, combined with the characteristic mutational spectrum induced by AA in TP53 and other genes provides compelling data for a role of AA in upper urothelial tract cancer.

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

Cited by 96 publications

References 56 publications

Hypermutation in human cancer genomes: footprints and mechanisms

Hypermutation in human cancer genomes: footprints and mechanisms

Aristolochic acid-associated urothelial cancer in Taiwan

New approaches for biomonitoring exposure to the human carcinogen aristolochic acid

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