Thesis title: The role of RNA-RNA interactions in the post-transcriptional control of cancer-related genes: the case of circHIPK3/BRCA1 mRNA pairing
Circular RNAs are covalently-closed transcripts often deregulated in cancer. While many studies describe circRNAs as miRNA sponges, we discovered a more direct mechanism of action involving circRNA-mRNA interaction. We showed that circHIPK3 regulates the levels of BRCA1 protein, an essential DNA-repair factor, through a direct interaction between the circRNA back-splicing-junction and BRCA1 mRNA. This interaction prevents the binding on the mRNA of FMRP protein, which we identified as a BRCA1 translational repressor. We confirmed this competitive model and we modulated it in different conditions to study phenotypic effects and possible therapeutic applications. We demonstrated that the disruption of circHIPK3-BRCA1 interaction induces DNA-damage accumulation, strengthens the effects of DNA damage-inducing drugs and sensitizes BRCA1 wild-type tumour cells to PARP inhibitors by synthetic lethality. On the other hand, the inhibition of FMRP/BRCA1 interaction with locked-nucleic acids restores physiological BRCA1 levels and prevents DNA-damage accumulation in BRCA1 hemizygous breast cancer cells.