Epidermal transit of replication-arrested, undifferentiated keratinocytes in UV-exposed XPC mice: An alternative to
            <i>in situ</i>
            apoptosis

Stout, Gerdine J.; Westdijk, Daniel; Calkhoven, Dennis M.; Pijper, Olaf; Backendorf, Claude; Willemze, Rein; Mullenders, Leon H.F.; Gruijl, Frank R. de

doi:10.1073/pnas.0505505102

Cited by 14 publications

(14 citation statements)

References 19 publications

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“…This indicates that tissue-wide signals to wild-type keratinocytes increase the rate of production of proliferating cells to compensate for cell loss through UVB-induced apoptosis. Previous studies provide strong evidence for the resistance of p53-mutated cells to apoptosis, growth arrest, or terminal differentiation induced by UVB (5,34). If both normal and p53 mutant progenitor cells respond equally to UVB by generating more proliferating cells, the reduced loss of p53-mutated cells will result in exponential growth, as there is an effective imbalance between the rate of mutant cell loss and self-duplication (Fig.…”

Section: Discussionmentioning

confidence: 99%

Stochastic fate ofp53-mutant epidermal progenitor cells is tilted toward proliferation by UV B during preneoplasia

Klein

Brash

Jones

et al. 2009

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

106

108

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UV B (UVB) radiation induces clones of cells mutant for the p53 tumor suppressor gene in human and murine epidermis. Here we reanalyze large datasets that report the fate of clones in mice subjected to a course of UVB radiation, to uncover how p53 mutation affects epidermal progenitor cell behavior. We show that p53 mutation leads to exponential growth of clones in UV-irradiated epidermis; this finding is also consistent with the size distribution of p53 mutant clones in human epidermis. Analysis of the tail of the size distribution further reveals that the fate of individual mutant cells is stochastic. Finally, the data suggest that ending UVB exposure results in the p53 mutant cells adopting the balanced fate of wild-type cells: the loss of mutant cells is balanced by proliferation so that the population of preneoplastic cells remains constant. We conclude that preneoplastic clones do not derive from long-lived, self-renewing mutant stem cells but rather from mutant progenitors with random cell fate. It follows that ongoing, low-intensity UVB radiation will increase the number of precancerous cells dramatically compared with sporadic, higherintensity exposure at the same cumulative dose, which may explain why nonmelanoma skin cancer incidence depends more strongly on age than on radiation dosage. Our approach may be applied to determine cell growth rates in clonally labeled material from a wide range of tissues including human samples.cancer | stem cells | stochastic fate

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Section: Discussionmentioning

confidence: 99%

Stochastic fate ofp53-mutant epidermal progenitor cells is tilted toward proliferation by UV B during preneoplasia

Klein

Brash

Jones

et al. 2009

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

106

108

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“…Interestingly, UV-exposed Xpc À/À and Xpc À/À G1-2Terc À/À skin displayed keratinocytes with aberrant differentiation (e.g., suprabasal cells cytokeratin 5 positive and cytokeratin 10 negative; Supplementary Fig. S6) suggesting that epidermal turnover may be responsible for removal of damaged cells (29). Next, the number p53 Ã patches (Fig.…”

Section: Immunohistochemistry On Uv-irradiated Skinmentioning

confidence: 99%

Telomere Length and Telomerase Activity Impact the UV Sensitivity Syndrome Xeroderma Pigmentosum C

Stout

Blasco

2013

Cancer Research

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Xeroderma pigmentosum (XP), a UV-sensitivity syndrome characterized by skin hyperpigmentation, premature aging, and increased skin cancer, is caused by defects in the nucleotide excision repair (NER) pathway. XP shares phenotypical characteristics with telomere-associated diseases like Dyskeratosis congenita and mouse models with dysfunctional telomeres, including mice deficient for telomerase (Terc À/À mice). Thus, we investigated a hypothesized role for telomerase and telomere dysfunction in the pathobiology of XP by comparing Xpc-mutant mice and Xpc À/À G1-G3Terc À/À double-mutant mice and exposed them to UV radiation.Chronically UV-exposed Xpc À/À skin displayed shorter telomeres on an average compared with wild-type skin.Strikingly, this effect was reversed by an additional deficiency in the telomerase. Moreover, aberrantly long telomeres were observed in the double-mutant mice. Telomere lengthening in the absence of telomerase suggested activation of the alternative lengthening of telomeres (ALT) in the UV-exposed skin of the double mutants. Mechanistic investigations revealed an elevated susceptibility for UV-induced p53 patches, known to represent precursor lesions of carcinomas, in Xpc À/À G1-G3Terc À/À mice where a high number of UV-induced skin tumors occurred that were characterized by aggressive growth. Taken together, our results establish a role for xeroderma pigmentosum, complementation group C (XPC) in telomere stability, particularly upon UV exposure. In absence of telomerase, critically short telomeres in XP mutants seem to aggravate this pathology, associated with an increased tumor incidence, by activating the ALT pathway of telomere lengthening. Cancer Res; 73(6);

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“…In both genotypes an S phase delay was induced early after UV exposure, evidenced by reduced BrdU incorporation per cell (population 3). At later time points, BrdU incorporation in many S-phase cells ceased completely (population 4), as shown before (16). Populations 3 ϩ 4 were transiently enlarged in the Rev1-mutant epidermis indicating a slightly increased S phase delay.…”

Section: Resultsmentioning

confidence: 78%

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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Epidermal transit of replication-arrested, undifferentiated keratinocytes in UV-exposed XPC mice: An alternative to in situ apoptosis

Cited by 14 publications

References 19 publications

Stochastic fate ofp53-mutant epidermal progenitor cells is tilted toward proliferation by UV B during preneoplasia

Stochastic fate ofp53-mutant epidermal progenitor cells is tilted toward proliferation by UV B during preneoplasia

Telomere Length and Telomerase Activity Impact the UV Sensitivity Syndrome Xeroderma Pigmentosum C

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

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