Differential role of transcription-coupled repair in UVB-induced response of human fibroblasts and keratinocytes.

Abstract

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/m(2), 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.

• Authors: Mariarosaria D'Errico, Massimo Teson, Angelo Calcagnile, Tiziana Nardo, Naomi De Luca, Chiara Lazzari, Silvia Soddu, Giovanna Zambruno, Miria Stefanini, Eugenia Dogliotti
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 2 Pg. 432-8 (Jan 15 2005) ISSN: 0008-5472 [Print] United States
• PMID: 15695384 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nuclear Proteins
• Proto-Oncogene Proteins
• Tumor Suppressor Protein p53
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Apoptosis (genetics, radiation effects)
• Cell Survival (genetics, radiation effects)
• DNA Damage
• DNA Repair (physiology)
• Fibroblasts (cytology, physiology, radiation effects)
• Genome, Human
• Humans
• Keratinocytes (cytology, physiology, radiation effects)
• Nuclear Proteins (genetics)
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins c-mdm2
• Skin Neoplasms (etiology, genetics)
• Transcription, Genetic (radiation effects)
• Transcriptional Activation
• Tumor Suppressor Protein p53 (genetics)
• Ultraviolet Rays