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TFIIH: when transcription met DNArepair
Emmanuel Compe and Jean-Marc Egly
Abstract | The transcription initiation factor TFIIH is a remarkable protein complex that has a fundamental role in the transcription of protein-coding genes as well as during the DNA nucleotide excision repair pathway. The detailed understanding of how TFIIH functions to coordinate these two processes is also providing an explanation for the phenotypes observed in patients who bear mutations in some of the TFIIH subunits. In this way, studies of TFIIH have revealed tight molecular connections between transcription and DNA repair and have helped to define the concept of transcription diseases.
Following gene activation, a host of proteins including RNA polymerase II (Pol II), general transcription factors, cofactors and chromatin-remodelling factors are assembled around the promoter and contribute to the accurate expression of protein-coding genes. In para llel, to maintain genome integrity and to ensure the continuation of transcription, DNA lesions that are caused by genotoxic agents have to be eliminated. This implies that there must be connections between the seemingly disparate events of transcription and DNA repair. A link between DNA repair and transcription was first suspected when it was found that the repair of DNA damage (in particular, ultraviolet (UV) light-induced cyclobutane pyrimidine dimers) is much faster and more efficient on the coding strand of active genes than on the other parts of the genome1,2. Several years later, the multi-protein complex transcription initiation factor TFIIH (BOX1) was found
to be indispensable during basal transcription and during nucleotide excision repair (NER) of DNA damage, thus revealing the functional link between these two processes3,4. The more recent demonstration that NER factors localize to the promoters of activated genes5,6
strengthens the idea of an interplay between NER and transcription and raises questions about how these factors might act in proximity to ongoing transcription in the absence of exogenous genotoxic attack.
The story of TFIIH started in 1989, when a factor named general transcription factor- (purified from rat liver)7 or basic transcription factor 2 (BTF2, purified from HeLa cells)8 was characterized as an indispensable transcription factor invitro. This factor was also isolated from yeast (termed yeast Pol II transcription factor b)9 and was finally designated TFIIH in 1992 (REF. 10). Peptide micro-sequencing revealed that TFIIH contains...