Oral communication, GL6

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

Xeroderma pigmentosum and trichothiodystrophy: understanding cancer and non cancer phenotypes

In devoting our research to the elucidation of the molecular mechanisms that control, at the transcriptional level, the expression of protein-coding genes (our real fundamental project), we found our group discovering the fantastic world of DNA repair. This started once we isolated TFIIH, a remarkable multi-subunit complex that was not only essential for several key steps in the transcription process, but also turned out to play an equally pivotal role in DNA repair and more precisely in Nucleotide Excision Repair (NER). To document its role, we systematically dissected and reconstructed the key molecular machines of TFIIH and tested their in vitro (biochemical) and in vivo (physiological) functions using a panel of assays that were designed up in our laboratory after having completely reconstituted and produced the recombinant multi-subunit TFIIH complex. Knowing that mutations in XPB, XPD, and p8/TTDA, three subunits of TFIIH led to xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS), we with the help of clinicians had tried to explain the molecular defects resulting from the various phenotypes e.g. photosensitivity, neuro-degeneration, lack of adipose tissue, ichtyosis, among others. Having realized that there might be a connection between DNA repair and transcription documented by the dual function of TFIIH, we next were surprised to find that RNA polymerase II transcription machinery assembles sequentially with the Nucleotide Excision Repair (NER) factors at the promoter of activated genes and this in absence of exogenous genotoxic attack. We presently document the role of these repair proteins at the promoter of activated genes in contributing to gene expression through their involvement in DNA de-methylation and/or histone post-translational modifications. Moreover we have extended our work by investigating the function of the Mediator that connect the DNA binding proteins to the basal transcription machinery. Mutations in the Mediator subunits results in several genetic disorders that share some clinical features with XP, TTD. Our work contributed not only to a better understanding of the gene expression regulation and the maintaining of genome integrity but also had explain some of the phenotypes of several genetic disorders, the hormonal regulation defects and the mechanism of anti-tumorigenic drugs. Such approaches were beneficial in understanding not only the function of TFIIH in both transcription and DNA repair, but also of all the other NER factors.

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