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Ruetze M.,Beiersdorf AG | Ruetze M.,Heinrich Pette Institute For Experimentelle Virologie Und Immunologie | Dunckelmann K.,Beiersdorf AG | Schade A.,Beiersdorf AG | And 6 more authors.
Journal of Dermatological Science | Year: 2011

Background: The epidermis harbors adult stem cells that reside in the basal layer and ensure the continuous maintenance of tissue homeostasis. Various studies imply that stem cells generally possess specific defense mechanisms against several forms of exogenous stress factors. As sun exposition is the most prevalent impact on human skin, this feature would be of particular importance in terms of sensitivity to UV-induced DNA damage. Objective: To investigate whether human epidermal stem cells are susceptible to UV-induced DNA damage and subsequent functional impairment. Methods: A method to isolate human epidermal stem cells from suction blister epidermis was established and validated. Volunteers were treated with solar-simulated irradiation on test areas of the forearm and stem cells were isolated from suction blister material of this region. DNA damage was analyzed by staining for cyclobutane thymidine dimers. The functional consequences of UV-induced damages were assessed by colony forming efficiency assays and gene expression analyses. Results: Compared to an unirradiated control, stem cells isolated from areas that were exposed to solar-simulated radiation showed significantly more DNA lesions. Although the number of stem cells was not reduced by this treatment, a functional impairment of stem cells could be shown by reduced colony forming efficiency and altered gene expression of stem cell markers. Conclusions: Despite their essential role in skin maintenance, epidermal stem cells are sensitive to physiological doses of UV irradiation in vivo. © 2011 Japanese Society for Investigative Dermatology. Source


Felle M.,University of Regensburg | Joppien S.,Ludwig Maximilians University of Munich | Nemeth A.,University of Regensburg | Diermeier S.,University of Regensburg | And 5 more authors.
Nucleic Acids Research | Year: 2011

Aberrant DNA methylation is often associated with cancer and the formation of tumors; however, the underlying mechanisms, in particular the recruitment and regulation of DNA methyltransferases remain largely unknown. In this study, we identified USP7 as an interaction partner of Dnmt1 and UHRF1 in vivo. Dnmt1 and USP7 formed a soluble dimer complex that associated with UHRF1 as a trimeric complex on chromatin. Complex interactions were mediated by the C-terminal domain of USP7 with the TS-domain of Dnmt1, whereas the TRAF-domain of USP7 bound to the SRA-domain of UHRF1. USP7 was capable of targeting UHRF1 for deubiquitination and affects UHRF1 protein stability in vivo. Furthermore, Dnmt1, UHRF1 and USP7 co-localized on silenced, methylated genes in vivo. Strikingly, when analyzing the impact of UHRF1 and USP7 on Dnmt1-dependent DNA methylation, we found that USP7 stimulated both the maintenance and de novo DNA methylation activity of Dnmt1 in vitro. Therefore, we propose a dual role of USP7, regulating the protein turnover of UHRF1 and stimulating the enzymatic activity of Dnmt1 in vitro and in vivo. © The Author(s) 2011. Published by Oxford University Press. Source


Sommer G.,Medical University of South Carolina | Dittmann J.,Medical University of South Carolina | Dittmann J.,Heinrich Pette Institute For Experimentelle Virologie Und Immunologie | Kuehnert J.,Medical University of South Carolina | And 7 more authors.
Oncogene | Year: 2011

The La protein is an essential RNA-binding protein implicated in different aspects of RNA metabolism. Herein, we report that small interfering (siRNA)-mediated La depletion reduces cell proliferation of different cell lines concomitant with a reduction in cyclin D1 (CCND1) protein. To exclude off-target effects we demonstrate that exogenous La expression in La-depleted cells restores cell proliferation and CCND1 protein levels. In contrast, proliferation of immortalized CCND1 knockout cells is not affected by La depletion, supporting a functional coherence between La, CCND1 and proliferation. Furthermore, we document by reversible in vivo crosslinking and ribonucleoprotein (RNP) immunoprecipitation an association of the La protein with CCND1 messengerRNA and that CCND1 internal ribosome entry site (IRES)-dependent translation is modulated by La protein level within the cell. In addition, we show elevated La protein expression in cervical cancer tissue and its correlation with aberrant CCND1 protein levels in cervical tumor tissue lysates. In conclusion, this study establishes a role of La in cell proliferation and CCND1 expression and demonstrates for the first time an overexpression of the RNA-binding protein La in solid tumors. © 2011 Macmillan Publishers Limited All rights reserved. Source

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