Pharmacological Inhibition Of The Transcription/Repair Factor Tfiih
Reference : PhD Frédéric COIN
Offer publication : April 5, 2016
The present project focuses on the 10 subunit multi-protein complex TFIIH of which XPB, p62, p52, p44, p34, and p8 build the core and CDK7, MAT1, and CYCLIN H formed the CAK complex; bridged to the core by XPD. Initially identified as a basal transcription factor of the Polymerase II (pol II) machinery, TFIIH plays a key role in nucleotide excision repair (NER) by opening DNA at damaged sites and recruiting additional repair
factors. The participation of TFIIH in pol I transcription has been identified ten years ago but its role in this process as well as the specific role of its enzymatic activities remains undefined (Compe and Egly, 2012). A major breakthrough in the recent years was the discovery of highly specific small molecules able to target subunits of TFIIH (Kwiatkowski et al., 2014) (Titov et al., 2011) (Alekseev et al., 2014). Such pharmacological inhibitors of
TFIIH are valuable tools (Villicana et al., 2014) in cancer therapy but also represent an interesting approach to reveal new role of TFIIH in transcription and repair as well as its regulation in these different processes. The aim of this project is to develop knowledge on the function and regulation of TFIIH
in transcription and repair by the mean of newly discovered and highly specific inhibitors, some of them discovered by our lab. Additionally, to provide the scientific community with additional valuable tools, we are developing/looking for small molecules able to modulate important drug-orphan subunits of TFIIH such as the helicase XPD or the TTDA subunit involved in genetic disorders.
PhD student will use three highly specific drugs targeting the TFIIH subunits XPB and CDK7 to unveil the function of these subunits in transcription and repair using in vitro and in vivo approaches. In parallel high through put screening using ad hoc chemical library will be used in collaboration with the platform of IGBMC to unveil inhibitors of the third enzymatic subunit of TFIIH, the helicase XPD. These drugs will represent valuable chemicals that will be test for their capacity to specifically kill cancer cells vs normal cells at a given concentration at it is the case for inhibitors of XPB or CDK7 (rfe).
Alternatively, these chemicals will be tested in vivo and in vitro for their capacity to increase efficiency of platinum-based chemotherapies. The rational behind this strategy is the capacity of the NER pathway to remove DNA damages induced by platinum and the fact that cancer cells show increased NER activity that limits the action of platinum treatment (Alekseev et al., 2014). Any chemical that may inhibit NER would increase platinum based efficiency (ref).
- COMPETENCES SOUHAITEES : Compétences en biologie moléculaires et cellulaires. notion de bioinformatique.
- EXPERTISES QUI SERONT ACQUISES AU COURS DE LA FORMATION : Criblage de molécules thérapeutiques à haut débit. Microscopie confocal. RT-PCR, ChIP..
Application Deadline : Dec. 31, 2016