Obiettivo Many studies of global gene expression focus solely on studying the transcriptome thereby only assessing mRNA abundance. However, transcription is only a single layer of gene expression and recently, the influence of post-transcriptional regulation has become undeniable. Rather underrepresented players in post-transcriptional control are G-quadruplexes (G4s). These stable structures can form guanine tetrads in DNA and RNA via p-p-stacking of several planar arrangements of four guanine bases stabilized by Hoogsteen hydrogen bonds and a central metal cation. Recent reports have pointed to an important regulatory role of G4 motives in key cellular functions including pre-mRNA processing, RNA turnover, mRNA transport thereby suggesting intriguing links to human diseases as cancer and neurological disorders. G4 structures in mRNAs seem to act as signaling components that constitute an own post-transcriptional operon. Recruitment of G4-specific RBPs then determines the ultimate fate of G4-containing mRNAs. Not many RBPs or upstream regulatory factors of G4s have been identified and the functional consequences of these interactions are not known. In this proposal I will address these questions. First, I will identify mRNAs that are differentially translated and/or stabilized in the presence of the G4 specific ligand pyridostatin (PDS), which stabilizes G4 structures. The resulting comprehensive list of mRNAs will be the first data set that provides a mechanistically link of G4 motive regulation. Secondly, I will identify factors in the G4 regulatory network using a genome wide shRNA assay to determine proteins that modulate the stability and/or the translation of G4 motive containing mRNAs. It is important to understand G4 structure-function relationships and upstream regulatory processes as the emerging link between G4 formation and human disease opens up an exciting research direction that has potential implications for therapeutic intervention. Campo scientifico natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticsRNAmedical and health sciencesbasic medicineneurologynatural sciencesbiological sciencesgeneticsgenomes Programma(i) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Argomento(i) MSCA-IF-2015-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Invito a presentare proposte H2020-MSCA-IF-2015 Vedi altri progetti per questo bando Meccanismo di finanziamento MSCA-IF-EF-ST - Standard EF Coordinatore THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE Contribution nette de l'UE € 183 454,80 Indirizzo TRINITY LANE THE OLD SCHOOLS CB2 1TN Cambridge Regno Unito Mostra sulla mappa Regione East of England East Anglia Cambridgeshire CC Tipo di attività Higher or Secondary Education Establishments Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 183 454,80
