Linking environmental carcinogen exposure to TP53 mutations in human tumours using the human TP53 knock-in (Hupki) mouse model

Kucab, Jill E.; Phillips, David H.; Arlt, Volker M.

doi:10.1111/j.1742-464x.2010.07676.x

Cited by 40 publications

(36 citation statements)

References 112 publications

(129 reference statements)

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“…Importantly, mutated adenosines were located exclusively on the non-transcribed strand, suggesting that dA-AL adducts on either strand are likely to be refractory to GG-NER, while adducts on the transcribed strand are repaired by TC-NER. A similar strand bias was observed in studies of Hupki mice exposed to AAI (33). Both the persistence of dA-AL adducts and the marked strand bias for A→T mutations suggest that dA-AL adducts are selectively repaired by TC-NER.…”

Section: Introductionsupporting

confidence: 79%

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

Sidorenko

Yeo

Bonala

et al. 2011

Nucleic Acids Research

109

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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.

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Section: Introductionsupporting

confidence: 79%

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

Sidorenko

Yeo

Bonala

et al. 2011

Nucleic Acids Research

109

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“…The p53 signaling pathway was commonly affected in both tissues (Tables 2 and 5) (Malik et al , 2012). p53 is a tumor suppressor protein, and mutations in the TP53 gene have been found in many types of human cancers linked to environmental exposures (Kucab et al , 2010) including lung cancers. The p53 protein is a transcription factor that mediates expression of several genes, including Cdkn1a , an inhibitor of cyclin-dependent kinases, Bax , a proapoptotic gene, Gadd45 , a DNA damage repair gene, which is also involved in cell cycle arrest, and many inflammatory modulators and growth factors.…”

Section: Discussionmentioning

confidence: 99%

Subchronic Oral Exposure to Benzo(a)pyrene Leads to Distinct Transcriptomic Changes in the Lungs That Are Related to Carcinogenesis

Labib

Yauk

Williams

et al. 2012

Toxicological Sciences

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We have previously shown that acute oral exposure to the environmental carcinogen benzo(a)pyrene (BaP) elicits comparable levels of DNA adducts, but distinct transcriptomic changes, in mouse lungs and livers, the two main BaP bioactivating organs. Oral BaP exposure is predominantly associated with lung cancer and not hepatic cancer in some animal models, suggesting that gene expression differences may provide insight into the drivers of tissue-specific carcinogenesis. In the present study, we examine pulmonary DNA adduct formation, lacZ mutant frequency, and mRNA profiles in adult male MutaMouse following subchronic (28 day) oral exposure to BaP (0, 25, 50, and 75mg/kg/day) and sacrificed 3 days postexposure. The results are compared with those obtained from livers of the same mice (previously published). Although there was a 1.8- to 3.3-fold increase in the levels of DNA adducts in lung compared with liver, the lacZ transgene mutant frequency was similar in both tissues. At the transcriptomic level, a transition from activation of the DNA damage response p53 pathway at the low dose to the induction of genes involved in angiogenesis, evasion of apoptosis and growth signals at the high doses was evident only in the lungs. These results suggest that tissue DNA adducts and mutant frequency are sensitive markers of target tissue exposure and mode of action, whereas early changes in gene expression may provide a better indication of the likelihood of carcinogenic transformation in selected tissues. Moreover, the study provides new information on the underlying mecha- nisms that contribute to tissue-specific responses to BaP.

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“…66,67 Multiple studies carried out in a variety of systems using different techniques ranging from the UvrABC nuclease incision method in combination with ligation-mediated PCR to mass spectrometry of specific isotopically labeled TP53 sequences demonstrate that PAH diol epoxide metabolites react preferentially at the TP53 hotspots observed in tobacco smoke associated lung cancers. [66][67][68][69][70][71] These results provide strong support for the involvement of PAH in lung cancer etiology in smokers. However, similar results have been reported in experiments with acrolein, which occurs in cigarette smoke in concentrations up to 10,000 times greater than those of BaP.…”

Section: Consequences Of Dna Adduct Formation-mutations In Critical Gmentioning

confidence: 99%

Lung carcinogenesis by tobacco smoke

Hecht

2012

Intl Journal of Cancer

376

284

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Cigarette smoke is a complex mixture of chemicals including multiple genotoxic lung carcinogens. The classic mechanisms of carcinogen metabolic activation to DNA adducts, leading to miscoding and mutations in critical growth control genes, applies to this mixture but some aspects are difficult to establish because of the complexity of the exposure. This paper discusses certain features of this mechanism including the role of nicotine and its receptors; lung carcinogens, co-carcinogens and related substances in cigarette smoke; structurally characterized DNA adducts in the lungs of smokers; the mutational consequences of DNA adduct formation in smokers’ lungs; and biomarkers of nicotine and carcinogen uptake as related to lung cancer. While there are still uncertainties which may never be fully resolved, the general mechanisms by which cigarette smoking causes lung cancer are well understood and provide insights relevant to prevention of lung cancer, the number one cancer killer in the world, causing 1.37 million deaths per year.

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Linking environmental carcinogen exposure to TP53 mutations in human tumours using the human TP53 knock-in (Hupki) mouse model

Cited by 40 publications

References 112 publications

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

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

Subchronic Oral Exposure to Benzo(a)pyrene Leads to Distinct Transcriptomic Changes in the Lungs That Are Related to Carcinogenesis

Lung carcinogenesis by tobacco smoke

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