Persistence of p53 mutations and resistance of keratinocytes to apoptosis are associated with the increased susceptibility of mice lacking the XPC gene to UV carcinogenesis

Ananthaswamy, Honnavara N.; Ouhtit, Allal; Evans, Robert B.; Gorny, Alexander; Khaskina, Polina; Sands, Arthur; Conti, Claudio J.

doi:10.1038/sj.onc.1203147

Cited by 25 publications

(19 citation statements)

References 27 publications

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“…Accordingly, apoptosis levels have been shown to be similar or lower in XPC fibroblasts or keratinocytes compared with wild-type cells following UVC 38 or UVB irradiation. 39 Similarly, Ananthaswamy et al 40 reported that XPC À/À mouse skin was more resistant to apoptosis following chronic UV irradiation than wild-type skin. The same levels of UV-induced apoptosis in XPC cells and normal cells are consistent with the idea that failure to repair UV damage (especially CPD) in the transcriptionally silent regions of the genome or in the non-transcribed strand of active genes does not induce apoptosis.…”

Section: Xpc Gene Defectmentioning

confidence: 99%

Catalase overexpression reduces UVB-induced apoptosis in a human xeroderma pigmentosum reconstructed epidermis

et al. 2008

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Xeroderma pigmentosum type C (XPC) is a rare autosomal recessive disorder that occurs due to inactivation of the XPC protein, an important DNA damage recognition protein involved in DNA nucleotide excision repair (NER). This defect, which prevents removal of a wide array of direct and indirect DNA lesions, is associated with a decrease in catalase activity. To test the hypothesis of a novel photoprotective approach, we irradiated epidermis reconstructed with XPC human keratinocytes sustainably overexpressing lentivirus-mediated catalase enzyme. Following UVB irradiation, there was a marked decrease in sunburn cell formation, caspase-3 activation and p53 accumulation in human XPC-reconstructed epidermis overexpressing catalase. Moreover, XPC-reconstructed epidermis was more resistant to UVB-induced apoptosis than normal reconstructed epidermis. While not correcting the gene defect, indirect gene therapy using antioxidant enzymes may be of help in limiting photosensitivity in XPC and probably in other monogenic/polygenic photosensitive disorders characterized by ROS accumulation.

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Section: Xpc Gene Defectmentioning

confidence: 99%

Catalase overexpression reduces UVB-induced apoptosis in a human xeroderma pigmentosum reconstructed epidermis

et al. 2008

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“…In NER-deficient mice, the prevalence of p53 mutations in the TS versus NTS is dependent on the specific pathway which is absent. Tumors of Xpc-deficient mice predominantly carry mutations in the NTS [115] and [120], whereas tumors of mice deficient in the Csb gene show predominantly p53 mutations in the TS [121]. Complete absence of NER -as found in Xpa −/− mice -results in the presence of p53 mutations in TS as well as NTS (70% and 30%, respectively) [121] and [122].…”

Section: Skinmentioning

confidence: 99%

Tissue specific mutagenic and carcinogenic responses in NER defective mouse models

Wijnhoven

Hoogervorst

Waard

et al. 2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Several mouse models with defects in genes encoding components of the nucleotide excision repair (NER) pathway have been developed. In NER two different sub-pathways are known, i.e. transcription-coupled repair (TC-NER) and global-genome repair (GG-NER). A defect in one particular NER protein can lead to a (partial) defect in GG-NER, TC-NER or both. GG-NER defects in mice predispose to cancer, both spontaneous as well as UV-induced. As such these models (Xpa, Xpc and Xpe) recapitulate the human xeroderma pigmentosum (XP) syndrome. Defects in TC-NER in humans are associated with Cockayne syndrome (CS), a disease not linked to tumor development. Mice with TC-NER defects (Csa and Csb) areexcept for the skin -not susceptible to develop (carcinogen-induced) tumors. Some NER factors, i.e. XPB, XPD, XPF, XPG and ERCC1 have functions outside NER, like transcription initiation and inter-strand crosslink repair. Deficiencies in these processes in mice lead to very severe phenotypes, like trichothiodystrophy (TTD) or a combination of XP and CS. In most cases these animals have a (very) short life span, display segmental progeria, but do not develop tumors. Here we will overview the available NER-related mouse models and will discuss their phenotypes in terms of (chemical-induced) tissue-specific tumor development, mutagenesis and premature aging features.

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“…To provide better evidence for a defect in error-prone TLS in vivo we determined the p53 mutation spectrum within SCC. In both genotypes C to T transitions predominated, typically at ''UV-fingerprint'' dipyrimidines (11,15; Table 1 and Fig. S1 A and B).…”

Section: Resultsmentioning

confidence: 99%

“…Genome Stability. Mutational inactivation of p53 precedes skin cancer (3,11,14). The Rev1 defect resulted in only a slight reduction of the number of p53-mutant patches in premalignant skin (Table 1) in apparent contrast with the phenotype of cultured Rev1 B/B cells.…”

Section: Resultsmentioning

confidence: 99%

Error-prone translesion replication of damaged DNA suppresses skin carcinogenesis by controlling inflammatory hyperplasia

Tsaalbi-Shtylik¹,

Verspuy²,

Jansen³

et al. 2009

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

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The induction of skin cancer involves both mutagenic and proliferative responses of the epidermis to ultraviolet (UV) light. It is believed that tumor initiation requires the mutagenic replication of damaged DNA by translesion synthesis (TLS) pathways. The mechanistic basis for the induction of proliferation, providing tumor promotion, is poorly understood. Here, we have investigated the role of TLS in the initiation and promotion of skin carcinogenesis, using a sensitive nucleotide excision repair-deficient mouse model that carries a hypomorphic allele of the error-prone TLS gene Rev1. Despite a defect in UV-induced mutagenesis, skin carcinogenesis was accelerated in these mice. This paradoxical phenotype was caused by the induction of inflammatory hyperplasia of the mutant skin that provides strong tumor promotion. The induction of hyperplasia was associated with mild and transient replicational stress of the UV-damaged genome, triggering DNA damage signaling and senescence. The concomitant expression of Interleukin-6 (IL-6) is in agreement with an executive role for IL-6 and possibly other cytokines in the autocrine induction of senescence and the paracrine induction of inflammatory hyperplasia. In conclusion, error-prone TLS suppresses tumor-promoting activities of UV light, thereby controlling skin carcinogenesis.DNA translesion synthesis ͉ Interleukin-6 ͉ skin cancer ͉ tumor initiation ͉ tumor promotion T umor initiation by mutagenic agents and tumor promotion by inflammatory agents are critical determinants of carcinogenesis. Ultraviolet light (UV) is considered a complete carcinogen, as it induces not only mutations but also a mild inflammatory and proliferative response of the skin, mediated by growth factors and inflammatory cytokines (1-3).Mutagenesis induced by DNA-damaging agents depends on specialized translesion synthesis (TLS) DNA polymerases that replicate damaged nucleotides, such as UV-induced photolesions, in an error-prone fashion. Thereby, TLS safeguards the perpetuation of replication on damaged templates at the expense of mutagenesis (4). Rev1 is a key actor in error-prone TLS (5). Although the protein can incorporate deoxycytosines opposite abasic nucleotides and some damaged guanines, Rev1 plays a regulatory, rather than a catalytic, role in error-prone TLS of other damages, including photolesions (5-7). The role of Rev1 in a particularly error-prone subpathway of TLS of photolesions is mediated by its N-terminal BRCT domain (6, 7). In agreement, mouse embryonic stem cells with a disruption of this domain (Rev1 B/B cells) lack all UV-induced nucleotide transversion mutations and part of the transitions (8). Nevertheless, this Rev1 allele is hypomorphic as in Rev1 B/B cells photolesions ultimately are replicated, in contrast to completely Rev1-deficient cells (7). Rev1 B/B mice display no spontaneous phenotypes, unlike completely Rev1-deficient mice, supporting the hypomorphic nature of the Rev1 B allele, also at endogenous DNA damages (8, 9).Here, we have investigated the premise that t...

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Persistence of p53 mutations and resistance of keratinocytes to apoptosis are associated with the increased susceptibility of mice lacking the XPC gene to UV carcinogenesis

Cited by 25 publications

References 27 publications

Catalase overexpression reduces UVB-induced apoptosis in a human xeroderma pigmentosum reconstructed epidermis

Catalase overexpression reduces UVB-induced apoptosis in a human xeroderma pigmentosum reconstructed epidermis

Tissue specific mutagenic and carcinogenic responses in NER defective mouse models

Error-prone translesion replication of damaged DNA suppresses skin carcinogenesis by controlling inflammatory hyperplasia

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