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TFIIH as a crucial actor in genome expression and repair

Objective

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 human genetics over the last decade, has been the realization that diseases such as cancer but also ageing stem from some dis-regulation in the expression and preservation of the genetic information. TFIIH is a multiprotein complex that is essential in transcription and DNA repair. Mutations in some of its subunits are responsible of a UV sensitivity phenotype in yeast and drosophila. In human, this results in the rare DNA repair deficient genetic disorder, xeroderma pigmentosum (XP), which is characterized by photosensitivity and an increased risk of skin cancers. Two further disorders involving mutation in TFIIH subunits, Cockayne syndrome (CS) and trichothiodystrophy (TTD) are also defective in repair of UV damage, but present quite different clinical features such as brittle hair, neurological and developmental retardation, middles sun sensitivity and no susceptibility to solar carcinogenesis. The clinical complexity of these syndromes cannot be explained solely by deficiencies in DNA repair and emerging evidences indicate that it may also result from a dys-regulation of the transcriptional program under the control of hormones. The goal of this proposal is to investigate the DNA repair/transcription disorders involving mutations in TFIIH. This research will not only assists afflicted XP, CS, TTD and normal individuals in prevention and ultimately cures of hormonal dependent diseases and cancer (the clinical point of view), but more generally will provide an improved understanding of the mechanisms that regulate the expression of protein coding genes and the maintenance of genome integrity (the fundamental research point of view).

Field of science

  • /medical and health sciences/basic medicine/medical genetics
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /natural sciences/biological sciences/genetics and heredity
  • /natural sciences/biological sciences/molecular biology
  • /medical and health sciences/clinical medicine/oncology/cancer
  • /natural sciences/biological sciences/genetics and heredity/genome
  • /medical and health sciences/clinical medicine/oncology/cancer/skin cancer

Call for proposal

ERC-2008-AdG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET MEDECINE
Address
Rue Laurent Fries 1
67404 Illkirch Graffenstaden
France
Activity type
Research Organisations
EU contribution
€ 1 997 000
Principal investigator
Jean-Marc Egly (Prof.)
Administrative Contact
Steve Brooks (Dr.)

Beneficiaries (1)

CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET MEDECINE
France
EU contribution
€ 1 997 000
Address
Rue Laurent Fries 1
67404 Illkirch Graffenstaden
Activity type
Research Organisations
Principal investigator
Jean-Marc Egly (Prof.)
Administrative Contact
Steve Brooks (Dr.)