UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice

Horst, Gijsbertus T. J. van der; Meira, Lisiane B.; Gorgels, Theo G. M. F.; Wit, Jan de; Velasco-Miguel, Susana; Richardson, James A.; Kamp, Yvonne; Vreeswijk, Maaike P.G.; Smit, Bep; Bootsma, D.; Hoeijmakers, Jan H.J.; Friedberg, Errol C.

doi:10.1016/s1568-7864(01)00010-6

Cited by 99 publications

(71 citation statements)

References 35 publications

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“…It is not the only case for development of mesenchymal skin tumors in UV-irradiated repair-deficient mice. It has been reported that corneal hemangiosarcomas were observed in Csa Ϫ/Ϫ Xpc Ϫ/Ϫ mice (67).…”

Section: Role For Pol In Prevention Of Uv-induced Mesenchymal Tumorsmentioning

confidence: 97%

UV-B Radiation Induces Epithelial Tumors in Mice Lacking DNA Polymerase η and Mesenchymal Tumors in Mice Deficient for DNA Polymerase ι

Ohkumo

Kondo

Yokoi

et al. 2006

Molecular and Cellular Biology

106

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DNA polymerase(Pol ) is the product of the Polh gene, which is responsible for the group variant of xeroderma pigmentosum, a rare inherited recessive disease which is characterized by susceptibility to sunlightinduced skin cancer. We recently reported in a study of Polh mutant mice that Pol is involved in the somatic hypermutation of immunoglobulin genes, but the cancer predisposition of Polh ؊/؊ mice has not been examined until very recently. Another translesion synthesis polymerase, Pol , a Pol paralog encoded by the Poli gene, is naturally deficient in the 129 mouse strain, and the function of Pol is enigmatic. Here, we generated Polh Poli doubledeficient mice and compared the tumor susceptibility of them with Polh-or Poli-deficient animals under the same genetic background. While Pol deficiency does not influence the UV sensitivity of mouse fibroblasts irrespective of Polh genotype, Polh Poli double-deficient mice show slightly earlier onset of skin tumor formation. Intriguingly, histological diagnosis after chronic treatment with UV light reveals that Pol deficiency leads to the formation of mesenchymal tumors, such as sarcomas, that are not observed in Polh ؊/؊ mice. These results suggest the involvement of the Pol and Pol proteins in UV-induced skin carcinogenesis.

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Section: Role For Pol In Prevention Of Uv-induced Mesenchymal Tumorsmentioning

confidence: 97%

UV-B Radiation Induces Epithelial Tumors in Mice Lacking DNA Polymerase η and Mesenchymal Tumors in Mice Deficient for DNA Polymerase ι

Ohkumo

Kondo

Yokoi

et al. 2006

Molecular and Cellular Biology

106

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“…The neurodegenerative symptoms in mice are generally milder than in human and the cancer burden higher, especially for Cs (van der Horst et al, 1997;van der Horst et al, 2002;Laposa et al, 2007b) and Xpa De Vries, 1997;Tanaka et al, 2001). Variations due to strain backgrounds are also factors, especially regarding life-shortening versus cancer risk (Li et al, 2007;Partridge and Gems, 2007).…”

Section: What Constitutes Feasible Therapeutic Targets?mentioning

confidence: 99%

Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging

Cleaver

Revet

2008

Mechanisms of Ageing and Development

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Cancer, aging, and neurodegeneration are all associated with DNA damage and repair in complex fashions. Aging appears to be a cell and tissue-wide process linked to the insulin-dependent pathway in several DNA repair deficient disorders, especially in mice. Cancer and neurodegeneration appear to have complementary relationships to DNA damage and repair. Cancer arises from surviving cells, or even stem cells, that have down-regulated many pathways, including apoptosis, that regulate genomic stability in a multi-step process. Neurodegeneration however occurs in nondividing neurones in which the persistence of apoptosis in response to reactive oxygen species is, itself, pathological. Questions that remain open concern: sources and chemical nature of naturally occurring DNA damaging agents, especially whether mitochondria are the true source; the target tissues for DNA damage and repair; do the human DNA repair deficient diseases delineate specific pathways of DNA damage relevant to clinical outcomes; if naturally occurring reactive oxygen species are pathological in human repair deficient disease, would anti-oxidants or anti-apoptotic agents be feasible therapeutic agent?

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“…To facilitate experimental research on the etiology of CS, we have previously generated animal models for CS-A and CS-B by complete inactivation of the mouse Csa gene (Csa Ϫ/Ϫ mice) (47) and by mimicking a specific truncation (as found in CS-B patient CS1AN) in the mouse Csb gene (Csb m/m mice) (48). Both mouse models display a specific TC-NER defect and show increased photosensitivity of the skin (47,48).…”

mentioning

confidence: 99%

“…Both mouse models display a specific TC-NER defect and show increased photosensitivity of the skin (47,48). In contrast to human CS patients, Csa Ϫ/Ϫ and Csb m/m mice display modest skin cancer susceptibility, which becomes apparent after chronic exposure of animals to daily doses of UV light (4,48).…”

mentioning

confidence: 99%

“…This paradox is well explained by the fact that UV-induced cyclobutane pyrimidine dimers are the major causative lesion for UV skin cancer (27) and that rodents lack efficient GG-NER for the removal of this lesion from the DNA and thus rely primarily on TC-NER (5). Other CS features, like growth failure and neurological abnormalities, are present only in a mild form (47,48). Interestingly, complete inactivation of NER (by concurrent inactivation of the Xpa gene) in the Csb m/m mouse dramatically aggravates the CS features (including premature aging).…”

mentioning

confidence: 99%

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Retinal Degeneration and Ionizing Radiation Hypersensitivity in a Mouse Model for Cockayne Syndrome

Gorgels

Pluijm

Brandt

et al. 2007

Molecular and Cellular Biology

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Mutations in the CSB gene cause Cockayne syndrome (CS), a DNA repair disorder characterized by UV sensitivity and severe physical and neurological impairment. CSB functions in the transcription-coupled repair subpathway of nucleotide excision repair. This function may explain the UV sensitivity but hardly clarifies the other CS symptoms. Many of these, including retinopathy, are associated with premature aging. We studied eye pathology in a mouse model for CS. Csb m/m mice were hypersensitive to UV light and developed epithelial hyperplasia and squamous cell carcinomas in the cornea, which underscores the importance of transcriptioncoupled repair of photolesions in the mouse. In addition, we observed a spontaneous loss of retinal photoreceptor cells with age in the Csb m/m retina, resulting in a 60% decrease in the number of rods by the age of 18 months. Importantly, when Csb m/m mice (as well as Csa ؊/؊ mice) were exposed to 10 Gy of ionizing radiation, we noticed an increase in apoptotic photoreceptor cells, which was not observed in wild-type animals. This finding, together with our observation that the expression of established oxidative stress marker genes is upregulated in the Csb m/m retina, suggests that (endogenous) oxidative DNA lesions play a role in this CS-specific premature-aging feature and supports the oxidative DNA damage theory of aging.

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UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice

Cited by 99 publications

References 35 publications

UV-B Radiation Induces Epithelial Tumors in Mice Lacking DNA Polymerase η and Mesenchymal Tumors in Mice Deficient for DNA Polymerase ι

UV-B Radiation Induces Epithelial Tumors in Mice Lacking DNA Polymerase η and Mesenchymal Tumors in Mice Deficient for DNA Polymerase ι

Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging

Retinal Degeneration and Ionizing Radiation Hypersensitivity in a Mouse Model for Cockayne Syndrome

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