This Article Full Text Full Text (PDF) Supplementary Data 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 Google Scholar Articles by Chiganças, V. Articles by Sarasin, A. PubMed PubMed Citation Articles by Chiganças, V. Articles by Sarasin, A.

Defective Transcription/Repair Factor IIH Recruitment to Specific UV Lesions in Trichothiodystrophy Syndrome

¹ Laboratory of Genetic Stability and Oncogenesis, Centre National de la Recherche Scientifique, Formation de Recherche en Evolution 2939, Institut Gustave Roussy, Université Paris-Sud, Villejuif, France; and ² DNA Repair Laboratory, Instituto de Ciências Biomédicas 2, Universidade de Sao Paulo, Sao Paulo, Brazil

Requests for reprints: Alain Sarasin, Centre National de la Recherche Scientifique, Formation de Recherche en Evolution 2939, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France. Phone: 33-1-42-11-63-34; Fax: 33-1-42-11-50-08. E-mail: vchigancas{at}gmail.com or sarasin{at}igr.fr.

Key Words: TFIIH • trichothiodystrophy • nucleotide excision repair • UV-induced lesions • photolyase

Most trichothiodystrophy (TTD) patients present mutations in the xeroderma pigmentosum D (XPD) gene, coding for a subunit of the transcription/repair factor IIH (TFIIH) complex involved in nucleotide excision repair (NER) and transcription. After UV irradiation, most TTD/XPD patients are more severely affected in the NER of cyclobutane pyrimidine dimers (CPD) than of 6-4-photoproducts (6-4PP). The reasons for this differential DNA repair defect are unknown. Here we report the first study of NER in response to CPDs or 6-4PPs separately analyzed in primary fibroblasts. This was done by using heterologous photorepair; recombinant adenovirus vectors carrying photolyases enzymes that repair CPD or 6-4PP specifically by using the energy of light were introduced in different cell lines. The data presented here reveal that some TTD/XPD mutations affect the recruitment of TFIIH specifically to CPDs, but not to 6-4PPs. This deficiency is further confirmed by the inability of TTD/XPD cells to recruit, specifically for CPDs, NER factors that arrive in a TFIIH-dependent manner later in the NER pathway. For 6-4PPs, we show that TFIIH complexes carrying an NH₂-terminal XPD mutated protein are also deficient in recruitment of NER proteins downstream of TFIIH. Treatment with the histone deacetylase inhibitor trichostatin A allows the recovery of TFIIH recruitment to CPDs in the studied TTD cells and, for COOH-terminal XPD mutations, increases the repair synthesis and survival after UV, suggesting that this defect can be partially related with accessibility of DNA damage in closed chromatin regions. [Cancer Res 2008;68(15):6074–83]