CE12 - Génétique, génomique et ARN

Functioning and dysfunctioning of the transcription/repair factor TFIIH – TFIIH

Submission summary

Complex gene regulatory networks govern organism development and homeostasis. Dysfunction of these networks impacts fundamental cellular functions, leading to many human diseases. The characterization of complexes involved in these fundamental cellular pathways, the study of their cellular dynamics and localisation and the way they evolve in a pathological context become major challenges of modern biology. Among the fundamental cellular complexes, TFIIH is at the cross roads of genome expression and repair. Mutations in three genes coding for TFIIH subunits give rise to three genetic disorders harbouring complex phenotypes. Therefore, a wealth of genetic information on TFIIH in humans can be exploited to understand the way this protein complex is participating in the maintenance of cell homeostasis. A consortium of four teams in strong synergy will implement a project with the aim to provide a new level of insight into structure and function of TFIIH. To this end, the consortium undertakes to characterize macromolecular assemblies of complexes involving TFIIH and its partners. We will focus on the dynamic of the complex at work in cells, the localisation of its different subunits and main partners at high resolution in normal or pathological context. In vitro, we will analyse the fine regulation of TFIIH enzymatic activities inside the complex and in relation with its partners. We will dissect the dysfunction implemented by disease-causing mutations on the complex and on its interaction with its partners. To successfully implement this project and achieve our goal, the consortium relies on the high scientific quality of the associated teams and will leverage its leading-edge expertise in genome editing, structural biology, biochemistry, and functional genomics. The project will also benefit from strong scientific platforms and services and will be facilitated by the unique multi-disciplinary expertise of the host institutions. Finally, this project, based on strong preliminary data, will also provide valuable tools to the scientific community. The social and scientific impact of this multi-scale study on TFIIH is high not only for patients with genetic disease-causing mutations in TFIIH but also for the healthy population since more and more acquired disorders are characterized as transcription and/or DNA repair syndromes

Project coordination

Frédéric COIN (Institut de génétique et de biologie moléculaire et cellulaire (UM 41 - UMR 7104 - UMR_S 1258))

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IGBMC Institut de génétique et de biologie moléculaire et cellulaire (UM 41 - UMR 7104 - UMR_S 1258)
IGBMC Institut de génétique et de biologie moléculaire et cellulaire (UM 41 - UMR 7104 - UMR_S 1258)
StrInG Structure et Instabilité des Génomes
IGBMC Institut de génétique et de biologie moléculaire et cellulaire (UM 41 - UMR 7104 - UMR_S 1258)

Help of the ANR 665,458 euros
Beginning and duration of the scientific project: December 2020 - 42 Months

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