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Molecular and Cellular Biology, November 2006, p. 8515-8526, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00807-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Differential Role of Basal Keratinocytes in UV-Induced Immunosuppression and Skin Cancer{triangledown}

Judith Jans ,1,{dagger},{ddagger} George A. Garinis,1,{ddagger} Wouter Schul,1,§ Adri van Oudenaren,2 Michael Moorhouse,3 Marcel Smid,4 Yurda-Gul Sert,1 Albertina van der Velde,1 Yvonne Rijksen,1 Frank R. de Gruijl,5 Peter J. van der Spek,3 Akira Yasui,6 Jan H. J. Hoeijmakers,1 Pieter J. M. Leenen,2 and Gijsbertus T. J. van der Horst1*

MGC, Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands,1 Department of Immunology, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands,2 Department of Bioinformatics, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands,3 Department of Medical Oncology, Josephine Nefkens Institute, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands,4 Department of Dermatology, Leiden University Medical Center, Sylvius Laboratory, 2300 RA Leiden, The Netherlands,5 Department of Molecular Genetics, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan6

Received 8 May 2006/ Returned for modification 12 June 2006/ Accepted 30 August 2006

Cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) comprise major UV-induced photolesions. If left unrepaired, these lesions can induce mutations and skin cancer, which is facilitated by UV-induced immunosuppression. Yet the contribution of lesion and cell type specificity to the harmful biological effects of UV exposure remains currently unclear. Using a series of photolyase-transgenic mice to ubiquitously remove either CPDs or 6-4PPs from all cells in the mouse skin or selectively from basal keratinocytes, we show that the majority of UV-induced acute effects to require the presence of CPDs in basal keratinocytes in the mouse skin. At the fundamental level of gene expression, CPDs induce the expression of genes associated with repair and recombinational processing of DNA damage, as well as apoptosis and a response to stress. At the organismal level, photolyase-mediated removal of CPDs, but not 6-4PPs, from the genome of only basal keratinocytes substantially diminishes the incidence of skin tumors; however, it does not affect the UVB-mediated immunosuppression. Taken together, these findings reveal a differential role of basal keratinocytes in these processes, providing novel insights into the skin's acute and chronic responses to UV in a lesion- and cell-type-specific manner.

* Corresponding author. Mailing address: MGC, Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. Phone: 31 10 4087455. Fax: 31 10 4089468. E-mail: g.vanderhorst{at}erasmusmc.nl.

{triangledown} Published ahead of print on 11 September 2006.

{dagger} J.J. and G.A.G. contributed equally to this work.

{ddagger} Present address: Department of Molecular and Cell Biology, University of California at Berkeley, 125 Koshland Hall, Berkeley, Calif.

§ Present address: Novartis, Institute of Tropical Disease, Singapore.

Molecular and Cellular Biology, November 2006, p. 8515-8526, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00807-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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