TFIIH: from transcription to clinic

Once a large proportion of the genes responsible for genetic disorders are identified in the post-genome era, the fundamental challenge is to establis h a genotype/phenotype relationship, Our aim is to explain how mutations in a given gene affect its enzymatic function and, in consequence, disturb th e life of the cell. Genome integrity is continuously threatened by the occu rrence of DNA damage arising from cellular exposure to irradiation and geno toxic chemicals. This mutagenic or potentially lethal DNA damage induces va rious cellular responses including cell cycle arrest, transcription alterat ion and processing by DNA repair mechanisms, such as the nucleotide excisio n repair (NER) pathway. Disruption of NER in response to genotoxic injuries results in autosomal recessive hereditary diseases such as Xeroderma pigme ntosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD), One of t he most immediate consequences of the induction of strand-distorting lesion s is the arrest of transcription in which TFIIH plays a role in addition to its role in DNA repair. The observations made by clinicians close to XP, T TD and CS patients, suggested that transcription defects responsible for br ittle hair and nails for TTD, or developmental abnormalities for CS, result ed from TFIIH mutations. Here a story will be related which could be called 'a multi-faceted factor named TFIIH', As biochemists, we have characterize d each component of TFIIH, three of which are XPB and XPD helicases and cdk 7, a cyclin-dependent kinase. With the help of structural biologists, we ha ve characterized most of the specific three-dimensional structures of TFIIH subunits and obtained its electron microscopy image. Together these approa ches help us to propose a number of structure-function relationships for TF IIH, Through transfection and microinjection assays, cell biology allows us to determine the role of TFIIH in transcription and NER, We are thus in a position to explain, at least in part, transcription initiation mechanisms and their coupling to DNA repair, We now know how the XPB helicase opens th e promoter region for RNA synthesis and that one of the roles of XPD helica se is to anchor the cdk7 kinase to the core-TFIIH. In XP and CS associated patients, we have demonstrated that some XPD mutations prevent an optimal p hosphorylation of nuclear receptors by cdk7 with, as a consequence, a drop in the expression of genes sensitive to hormone action. We have thus shown that hormonal responses operate through TFIIH, Careful analysis of each TFI IH subunit also shows how the p44 Ring finger participates in certain promo ter escape reactions. We are also able to localize the action of TFIIH in t he sequence of events that lead to the elimination of DNA lesions. Thanks t o the combination of these different approaches we are obtaining a much cle arer picture of the TFIIH complex and its integration into the life of the cell, (C) 2001 Federation of European Biochemical Societies. Published by E lsevier Science B.V. All rights reserved.