Une pipeline originale pour cribler des molécules ciblant les facteurs d'épissage

par Asaki Kobayashi (Lejars)

Projet de thèse en Sciences de la vie et de la santé

Sous la direction de David PastrÉ et de Alexandre Maucuer.

Thèses en préparation à Paris Saclay , dans le cadre de Structure et Dynamique des Systèmes Vivants , en partenariat avec Structure et Activité des Biomolécules Normales et Pathologiques (laboratoire) et de université d'Evry-Val-d'Essonne (établissement de préparation de la thèse) depuis le 01-09-2017 .


  • Résumé

    Cette thèse porte sur le développement de molécules ciblant les facteurs d'épissage. Notre approche sera basée sur des données structurales obtenues par spectroscopie RMN et par des approches cellulaires (QPCR, rapporteur d'épissage, ETC...). Nous travaillerons particulièrement sur un complexe formé par deux facteurs d'épissage qui a déjà été identifié au laboratoire. La société SYNSIGHT, grâce à ses outils de dynamique moléculaire, nous permettra de cribler des molécules en s'appuyant sur les données structurales obtenues par spectroscopie RMN.

  • Titre traduit

    An original pipeline to screen drugs targeting splicing factors


  • Résumé

    Pre-mRNA splcing consists in the removal of intermediary sequences from pre-messenger RNAs to yield mature messenger RNAs that can be exported form the nucleus and translated into functional proteins. It follows that pre-mRNA splicing defects have dramatic consequences on protein expression. Indeed genetic diseases are often associated with mutations of RNA sequences recognized by the splicing machinery (the spliceosome) or by mutation or abnormal expression of some of its components, the spliceosomal RNA-Binding Proteins (RBPs). However, despite the evidence for the pervasive role of splicing defects in diseases, only few molecules that target the spliceosome have been detected by exome sequencing, some splicing inhibitors were initially identified as anti-cancer compounds and were shown to preferentially inhibit cancer cells proliferation. Splicing modulators are therefore promising drugs in particular for cancer therapy. We previously characterized a common interaction motif among splicing factors at the structural and at the functional level in a close collaboration with Dr Clara Kielkopf at the University of Rochester. These interactions that have been coined "UHM-ULM" interactions are involved in essential splicing events as well as regulations of exon inclusion. As part of the worldwide effort to understant the molecular mechanisms that underlie pre-mRNA splicing, our laboratory further dissects the implication of these interactions in normal cells and in the disease state. Actually UHM and ULM containing splicing factors have recently been associated with both cancer and neurodevelopmental syndromes. In this project we plan to identify molecules that interfere with these UHM-ULM interactions. These drugs will be part of the toolkit to decipher the particular function of each UHM-ULM interaction in splicing, their importance for cell proliferation and differentiation, tumor formation and maintenance, as well as tumor cell migration and invasion in the animal. These drugs will also be evaluated as candidates to modulate splicing in human pathologies.