Final Report Summary - TRANSREACT (TFIIH as a crucial actor in genome expression and repair)
Understanding how the genetic information of a cell is retrieved but also protected from insults is a major challenge facing modern molecular biology. Indeed, one of the most important developments in biomedical genetics over the last decade has been the realization that diseases such as cancer but also ageing stem from deregulation in the expression and preservation of the genetic information. Cell-type specificity in multicellular organisms results from differential gene expression. The aim of our project was to understand the complex network of interactions between the proteins that lead to gene expression regulation. Although there are many cellular processes that control gene expression, the most direct regulation occurs during transcription initiation. In eukaryotes, the combinatorial use of more than 200 proteins is required for the synthesis of a single messenger RNA by the RNA Polymerase II. Basically, besides Pol II, the transcription of encoding genes requires general transcription factors whose activity is controlled by co-activators and co-repressors. One of the co-activators is the Mediator, a large complex that interacts directly with the basal factor TFIIH thereby transmitting regulatory signals from gene-specific transcription factors to the general transcription machinery. Mutations in some of these components give rise to genetic disorders the investigations of the mechanistic defects of which have been beneficial in understanding their function in NER transcription.
Gene expression is jeopardized by genotoxic stress that challenges genome integrity and requires the function of several DNA repair pathways to remove DNA lesions. This implies that connections exist between the seemingly disparate events of transcription and DNA repair to orchestrate the expression and repair of genes. We have shown that DNA repair proteins are part of the transcription machinery and would, in addition to their role in preserving genome integrity, participate in gene expression likely by triggering chromatin modification. As examples, we have underlined the essential role of XPG and XPF NER factors in the chromatin loop organization required for optimal expression of activated genes, explaining at least partially the severe phenotypes of the Xeroderma pigmentosum/Trichothiodystrophy patients defective in these two proteins. We also have demonstrated the role of CSB another NER factor in removing some gene repressor following UV irradiation; Consequently we were able to provide explanation for the RNA synthesis arrest in cells from Cockayne syndrome patients. We also demonstrated how a mutation in the Mediator that co-segregates with non-syndromic autosomal recessive intellectual disability alter its role of adaptor between transcription factors bound at upstream responsive elements and Pol II. In addition to have improved our understanding of gene expression regulation (Compe, 2012), the knowledge and the technology developed during this project lead to a better understanding of the aetiology of the phenotypes of the diseases and help for developing diagnostic and therapy. During this period of time, we have proposed some molecules for cancer therapy.
Gene expression is jeopardized by genotoxic stress that challenges genome integrity and requires the function of several DNA repair pathways to remove DNA lesions. This implies that connections exist between the seemingly disparate events of transcription and DNA repair to orchestrate the expression and repair of genes. We have shown that DNA repair proteins are part of the transcription machinery and would, in addition to their role in preserving genome integrity, participate in gene expression likely by triggering chromatin modification. As examples, we have underlined the essential role of XPG and XPF NER factors in the chromatin loop organization required for optimal expression of activated genes, explaining at least partially the severe phenotypes of the Xeroderma pigmentosum/Trichothiodystrophy patients defective in these two proteins. We also have demonstrated the role of CSB another NER factor in removing some gene repressor following UV irradiation; Consequently we were able to provide explanation for the RNA synthesis arrest in cells from Cockayne syndrome patients. We also demonstrated how a mutation in the Mediator that co-segregates with non-syndromic autosomal recessive intellectual disability alter its role of adaptor between transcription factors bound at upstream responsive elements and Pol II. In addition to have improved our understanding of gene expression regulation (Compe, 2012), the knowledge and the technology developed during this project lead to a better understanding of the aetiology of the phenotypes of the diseases and help for developing diagnostic and therapy. During this period of time, we have proposed some molecules for cancer therapy.