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

Author:

Jans Judith1,Garinis George A.1,Schul Wouter1,van Oudenaren Adri2,Moorhouse Michael3,Smid Marcel4,Sert Yurda-Gul1,van der Velde Albertina1,Rijksen Yvonne1,de Gruijl Frank R.5,van der Spek Peter J.3,Yasui Akira6,Hoeijmakers Jan H. J.1,Leenen Pieter J. M.2,van der Horst Gijsbertus T. J.1

Affiliation:

1. MGC, Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands

2. Department of Immunology, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands

3. Department of Bioinformatics, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands

4. Department of Medical Oncology, Josephine Nefkens Institute, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands

5. Department of Dermatology, Leiden University Medical Center, Sylvius Laboratory, 2300 RA Leiden, The Netherlands

6. Department of Molecular Genetics, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan

Abstract

ABSTRACT 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.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

Reference46 articles.

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3. Boonstra, A., A. van Oudenaren, M. Baert, H. van Steeg, P. J. Leenen, G. T. van der Horst, J. H. Hoeijmakers, H. F. Savelkoul, and J. Garssen. 2001. Differential ultraviolet-B-induced immunomodulation in XPA, XPC, and CSB DNA repair-deficient mice. J. Investig. Dermatol.117:141-146.

4. Bootsma, D., K. H. Kraemer, J. E. Cleaver, and J. H. J. Hoeijmakers. 2001. Nucleotide excision repair syndromes: xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy, p. 677-703. In C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle (ed.), The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, N.Y.

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