BRCA1 levels and DNA-damage response are controlled by the competitive binding of circHIPK3 or FMRP to the BRCA1 mRNA

Abstract

Circular RNAs (circRNAs) are covalently closed RNA molecules widely expressed in eukaryotes and deregulated in several pathologies, including cancer. Many studies point to their activity as microRNAs (miRNAs) and protein sponges; however, we propose a function based on circRNA-mRNA interaction to regulate mRNA fate. We show that the widely tumor-associated circHIPK3 directly interacts in vivo with the BRCA1 mRNA through the back-splicing region in human cancer cells. This interaction increases BRCA1 translation by competing for the binding of the fragile-X mental retardation 1 protein (FMRP) protein, which we identified as a BRCA1 translational repressor. CircHIPK3 depletion or disruption of the circRNA-mRNA interaction decreases BRCA1 protein levels and increases DNA damage, sensitizing several cancer cells to DNA-damage-inducing agents and rendering them susceptible to synthetic lethality. Additionally, blocking FMRP interaction with BRCA1 mRNA with locked nucleic acid (LNA) restores physiological protein levels in BRCA1 hemizygous breast cancer cells, underscoring the importance of this circRNA-mRNA interaction in regulating DNA-damage response.