This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by D'Errico, M. Articles by Dogliotti, E. Search for Related Content PubMed PubMed Citation Articles by D'Errico, M. Articles by Dogliotti, E.

Differential Role of Transcription-Coupled Repair in UVB–Induced Response of Human Fibroblasts and Keratinocytes

¹ Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena, Rome, Italy; ² Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IRCCS, Via dei Monti di Creta, Rome, Italy; ³ Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso, Pavia, Italy; and ⁴ Molecular Oncogenesis Laboratory, Department of Experimental Oncology, Regina Elena Cancer Institute, Rome, Italy

Requests for reprints: Eugenia Dogliotti, Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Phone: 39-064990-2580; Fax: 39-064990-3650; E-mail: dogliott{at}iss.it.

Most solar radiation–induced skin cancers arise in keratinocytes. In the human epidermis, protection against cancer is thought to be mediated mainly by nucleotide excision repair (NER) of UVB-induced cyclobutane pyrimidine dimers, and by elimination of the damaged cells by apoptosis. NER consists of two subpathways: global genome repair (GGR) and transcription-coupled repair (TCR). Here, we investigate the impact of defects in NER subpathways on the cellular response to UVB-induced damage by comparing primary human keratinocytes and fibroblasts from normal, XP-C (GGR-defective), and CS-A (TCR-defective) individuals. We show that human keratinocytes are more resistant to UVB killing than fibroblasts and present higher levels of UVB-induced DNA repair synthesis due to a more efficient GGR. The CS-A defect is associated with a strong apoptotic response in fibroblasts but not in keratinocytes. Following an UVB dose of 1,000 J/m², no p53-mediated transactivation of mdm2 is observed in CS-A fibroblasts, whereas the p53-mdm2 circuit is fully activated in CS-A keratinocytes. Thus, in fibroblasts, the signal for apoptosis originates from DNA photoproducts in the transcribed strand of active genes, whereas in keratinocytes, it is largely TCR-independent. This study shows that the response to UVB radiation is cell type–specific in humans and provides the first evidence that a deficiency in TCR has a different impact depending on the cell type. These findings have important implications for the mechanism of skin cancer protection after UVB damage and may explain the lack of skin cancer in patients with Cockayne syndrome.

Key Words: DNA repair • apoptosis • keratinocytes • UVB photoproducts • p53 response

This article has been cited by other articles:

				J.-O. Andressoo, G. Weeda, J. de Wit, J. R. Mitchell, R. B. Beems, H. van Steeg, G. T. J. van der Horst, and J. H. Hoeijmakers An Xpb Mouse Model for Combined Xeroderma Pigmentosum and Cockayne Syndrome Reveals Progeroid Features upon Further Attenuation of DNA Repair Mol. Cell. Biol., March 1, 2009; 29(5): 1276 - 1290. [Abstract] [Full Text] [PDF]

				B. E. Ferguson-Yates, H. Li, T. K. Dong, J. L. Hsiao, and D. H. Oh Impaired repair of cyclobutane pyrimidine dimers in human keratinocytes deficient in p53 and p63 Carcinogenesis, January 1, 2008; 29(1): 70 - 75. [Abstract] [Full Text] [PDF]

				J. O. Moore, Y. Wang, W. G. Stebbins, D. Gao, X. Zhou, R. Phelps, M. Lebwohl, and H. Wei Photoprotective effect of isoflavone genistein on ultraviolet B-induced pyrimidine dimer formation and PCNA expression in human reconstituted skin and its implications in dermatology and prevention of cutaneous carcinogenesis Carcinogenesis, August 1, 2006; 27(8): 1627 - 1635. [Abstract] [Full Text] [PDF]

				T. Maeda, R. A. Espino, E. G. Chomey, L. Luong, A. Bano, D. Meakins, and V. A. Tron Loss of p21WAF1/Cip1 in Gadd45-deficient keratinocytes restores DNA repair capacity Carcinogenesis, October 1, 2005; 26(10): 1804 - 1810. [Abstract] [Full Text] [PDF]