The interphase between dna damage repair and transcription

All organisms have evolved an intricate network of complementary DNA repair systems, to cope with DNA damage induced by endogenous or exogenous genotoxic agents These systems are crucial to ensure genetic stability and prevent mutagenesis and carcinogenesis. The nucleotide excision repair (NER) pathway for 'elimination of UV-induced lesions is understood in great detail and is associated with three clinically and genetically heterogeneous human syndromes characterized by marked sun sensitivity: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). XP patients show an over lOOOx increased risk of skin cancer, in contrast to CS and TTD. The latter disorders display severe developmental abnormalities and neurodysfunction. In addition TTD is characterized by brittle hair and nails, due to a reduced synthesis of cysteine-rich matrix proteins. At least 10 genes are involved, virtually all of which have been cloned. Some of the encoded proteins appeared also implicated in other cellular processes, explaining puzzling clinical features associated with defects in these genes. The proteins defective in TTD and in 2 of the complementation groups with combined XP/CS reside in the TFHH complex, involved in basal transcription and in NER. Many of the CS and TTD features may be due to a crippled TFIIH transcription function, affecting the expression of a specific set of genes. To understand the complex genotypephenotype relationship we have generated mouse models by gene targeting in embryonal stem cells. The present knowledge of the mechanism and biological impact of this and other damage repair pathways will be summarized.