Cancer predisposition, carcinogen hypersensitivity, and aberrant DNA metabolism

Paterson, M. C.; Gentner, N. E.; Middlestadt, M. V.; Weinfeld, Michael

doi:10.1002/jcp.1041210408

Cited by 44 publications

(17 citation statements)

References 45 publications

(47 reference statements)

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“…Like UV photolesions, 4NQO-DNA adducts are removed by the nucleotide excision repair pathway in normal human cells. Although there is a significant overlap in the repair pathways operating on UV-and 4NQO-induced lesions (20), differences have also been reported. Cells belonging to XP complementation group E, for example, exhibit normal levels of repair after 4NQO treatment, but defective repair in response to UV light (23,24).…”

Section: Introductionmentioning

confidence: 96%

“…Cells belonging to XP complementation group E, for example, exhibit normal levels of repair after 4NQO treatment, but defective repair in response to UV light (23,24). On the other hand, cells from AT patients show normal repair of UV photoproducts but defective repair of 4NQO-DNA adducts (20,25). In addition to bulky DNA lesions, 4NQO generates substantial amounts of active oxygen species in the cell, thereby producing DNA single-strand breaks (but not doublestrand breaks) and alkali-labile sites (26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

“…Herein, we compare the induction of p53 in human dermal fibroblast strains from normal, AT and XP donors following treatment with 4-nitroquinoline 1-oxide (4NQO), an extensively studied model environmental carcinogen whose DNAdamaging properties encompass those of both UV and ionizing radiation (20). 4NQO requires metabolic activation to be converted to the ultimate carcinogen 4-acetoxyaminoquinoline 1-oxide (21).…”

Section: Introductionmentioning

confidence: 99%

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Inverse correlation between p53 protein levels and DNA repair efficiency in human fibroblast strains treated with 4-nitroquinoline 1-oxide: evidence that lesions other than DNA strand breaks trigger the p53 response

et al. 1999

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Ionizing radiation-induced stabilization and the resultant transient accumulation of the p53 tumor suppressor protein is impaired in cells from ataxia telangiectasia (AT) patients, indicating a key role for ATM, the gene mutated in AT, upstream in the radiation-responsive p53 signaling pathway. Activation of this pathway is generally assumed to be triggered by DNA strand breaks produced directly following genotoxic stress or indirectly during excision repair of DNA lesions. The aim of this study was to identify the triggering signal for induction of p53 in diploid human dermal fibroblasts treated with 4-nitroquinoline 1-oxide (4NQO), a model environmental carcinogen that produces both DNA strand breaks (like ionizing radiation) and alkali-stable bulky DNA lesions (like UV light). 4NQO treatment of fibroblasts cultured from normal and AT donors and those from patients with the UV-hypersensitivity disorder xeroderma pigmentosum (XP, complementation groups A, E and G) resulted in up-regulation of p53 protein. In normal fibroblasts, there was no temporal relationship between the incidence of DNA strand breaks and levels of p53 protein; >90% of strand breaks and alkali-labile sites were repaired over 2 h following treatment with 1 µM 4NQO, whereas~3 h of post-treatment incubation was required to demonstrate a significant rise in p53 protein. In contrast, exposure of normal fibroblasts to γ-rays resulted in a rapid up-regulation of p53 and the level peaked at 2 h post-irradiation. XP cells with a severe deficiency in the nucleotide excision repair pathway showed abnormally high levels of p53 protein in response to 4NQO treatment, indicating that lesions other than incisionassociated DNA strand breaks trigger p53 up-regulation. We observed a consistent, inverse correlation between the ability of the various fibroblast cultures to induce p53 following 4NQO treatment and their DNA repair efficiencies. Treatment with 0.12 µM 4NQO, for example, caused a >2-fold up-regulation of p53 in excision repair-deficient (AT, XPA and XPG) strains without eliciting any effect on p53 levels in repair-proficient (normal and XPE) strains. We conclude that up-regulation of p53 by 4NQO is mediated solely by an ATM-independent mechanism and that the p53 response is primarily triggered by persistent alkalistable 4NQO-DNA adducts.Abbreviations: AT, ataxia telangiectasia; dThd, thymidine; 4NQO, 4-nitroquinoline 1-oxide; XP, xeroderma pigmentosum.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inverse correlation between p53 protein levels and DNA repair efficiency in human fibroblast strains treated with 4-nitroquinoline 1-oxide: evidence that lesions other than DNA strand breaks trigger the p53 response

et al. 1999

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“…Other clinical features of XP include blistering or freckling on minimal sun exposure, premature aging of skin, lips, eyes, mouth and tongue, blindness, progressive neurological complications such as developmental disabilities and mental retardation [44][45][46]. Cells cultured from XP patients are hypersensitive to UV in terms of cell killing, mutagenesis and in vitro transformation [44,47,48]. Eight genetic forms of XP have been identified, designated groups A through G, that are deficient in early steps of nucleotide excision repair (NER), and group variant, that is deficient in postreplication repair.…”

Section: Sunlight Hypersensitivity Disordersmentioning

confidence: 99%

Human Genetic Disorders Associated with Genome Instability, Premature Aging and Cancer Predisposition

Mirzayans¹,

Murray²

2008

TOCJ

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Our genetic material is constantly damaged by internal sources such as reactive oxygen species and external sources such as ionizing radiation and sunlight. However, we seldom notice these injuries because our cells possess elegant DNA surveillance networks that serve to maintain cellular homeostasis. These networks are complex signal transduction pathways that coordinate cell cycle checkpoints and DNA repair processes to eliminate DNA damage, as well as invoking pathways such as sustained growth arrest (i.e., accelerated senescence) and apoptotic cell death to eliminate injured cells from the proliferating population. The p53 tumor suppressor protein and its downstream effector p21 are key regulators of these various responses. Failure of cells to properly activate p53/p21-mediated events following genotoxic stress may lead to the development of genomic instability and the emergence of malignant cells which exhibit stem cell-like properties. It is therefore not surprising that defects in major players of the DNA surveillance networks are the underlying cause for numerous debilitating human genetic disorders that are characterized by genomic instability, premature aging, and cancer proneness. In this article, we first provide an update on the role of the p53 signaling pathway in determining the fate of human cells following exposure to DNA-damaging agents. We next review the clinical and laboratory features of the most extensively studied human genome instability disorders including xeroderma pigmentosum, Cockayne syndrome, ataxia telangiectasia, and Li-Fraumeni syndrome, and discuss the current knowledge on the biological consequences of deregulated p53 signaling in cells derived from patients with such disorders.

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“…Xeroderma pigmentosum (XP) is a human autosomalrecessive disease that occurs at a frequency of one to four per million live births and has an estimated carrier frequency of 0.2-0.4% in the general population (1). Homozygotes exhibit extreme photosensitivity leading to the occurrence of xerosis, pigmentation, and multiple skin carcinomas (2).…”

mentioning

confidence: 99%

Molecular cloning and characterization of a mammalian excision repair gene that partially restores UV resistance to xeroderma pigmentosum complementation group D cells.

Arrand¹,

Bone²,

Johnson³

1989

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

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A hamster DNA repair gene has been isolated by cosmid rescue after two rounds of transfection of an immortalized xeroderma pigmentosum (XP) complementation group D cell line with neomycin-resistance gene (neo)-tagged normal hamster DNA and selection with G418 and ultraviolet irradiation. The functional length of the sequence has been defined as 11.5 kilobase pairs by measurement of the region of overlap between two hamster DNA-containing cosmids, cloned by selection for the integrated neo gene, that are able to confer an increase in resistance to ultraviolet irradiation on two XP-D cell lines but not on an XP-A line. Detailed molecular characterization of the hamster repair gene has revealed no obvious similarities to two human excision repair genes (ERCCI and ERCC2) that correct repair-defective hamster cells but have no effect on XP cells. Hybridization analyses of normal human and XP cell genomic DNAs and mRNAs, using a cosmid-clone probe from which repeated sequences have been removed, show that homologues are present and expressed in all cases.Xeroderma pigmentosum (XP) is a human autosomalrecessive disease that occurs at a frequency of one to four per million live births and has an estimated carrier frequency of 0.2-0.4% in the general population (1). Homozygotes exhibit extreme photosensitivity leading to the occurrence of xerosis, pigmentation, and multiple skin carcinomas (2). Nine XP complementation groups have been described that display the characteristic XP biochemical defect in the incision step of UV-induced excision repair (3). The occurrence of many complementation groups sharing a common phenotypic defect indicates the existence of a large protein complex responsible for all steps in the excision repair of UV damage but in which damage to any component reduces the activity ofthe whole complex. Components of repair complexes from cells of various XP groups have been partially purified and shown to assemble into active complexes in in vitro complementation assays (4). A similar but smaller complex has been well characterized in bacteria (5), and the yeast Saccharomyces cerevisiae has 11 genes implicated in UV excision repair (3).In addition to the XP mutants, eight complementation groups have been found among UV-sensitive hamster and mouse cell lines (6); none overlaps with any human XP group tested (7) but groups 1, 2, 3, and 6 have been crosscomplemented by human genes ERCCI, ERCC2, ERCC3, and ERCC6 (8-10). However, no ERCC gene tested so far has any effect on the XP complementation groups (10-12).To isolate mammalian genes that correct XP cells, primary skin fibroblasts of many of the XP complementation groups have been immortalized by simian virus 40 (SV40) transformation (13)(14)(15)(16) (23) with a 16-hr exposure to DNA and with a 48-hr expression period before subculture into medium containing G418 (450-800 pug/ml).Forty-eight hours later, individual plates were trypsinized and irradiated in suspension in isotonic phosphate-buffered saline (PBS)/1% fetal calf serum with UV (7 J/m2)...

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Cancer predisposition, carcinogen hypersensitivity, and aberrant DNA metabolism

Cited by 44 publications

References 45 publications

Inverse correlation between p53 protein levels and DNA repair efficiency in human fibroblast strains treated with 4-nitroquinoline 1-oxide: evidence that lesions other than DNA strand breaks trigger the p53 response

Inverse correlation between p53 protein levels and DNA repair efficiency in human fibroblast strains treated with 4-nitroquinoline 1-oxide: evidence that lesions other than DNA strand breaks trigger the p53 response

Human Genetic Disorders Associated with Genome Instability, Premature Aging and Cancer Predisposition

Molecular cloning and characterization of a mammalian excision repair gene that partially restores UV resistance to xeroderma pigmentosum complementation group D cells.

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