Functional screen identifies RBM42 as a mediator of oncogenic mRNA translation specificity

Abstract

Oncogenic protein dosage is tightly regulated to enable cancer formation but how this is regulated by translational control remains unknown. The Myc oncogene is a paradigm of an exquisitely regulated oncogene and a driver of pancreatic ductal adenocarcinoma (PDAC). Here we use a CRISPR interference screen in PDAC cells to identify activators of selective MYC translation. The top hit, the RNA-binding protein RBM42, is highly expressed in PDAC and predicts poor survival. We show that RBM42 binds and selectively regulates the translation of MYC and a precise suite of pro-oncogenic transcripts, including JUN and EGFR. Mechanistically, we find that RBM42 binds and remodels the MYC 5′ untranslated region structure, facilitating the formation of the translation pre-initiation complex. Importantly, RBM42 is necessary for PDAC tumorigenesis in a Myc-dependent manner in vivo. This work transforms the understanding of the translational code in cancer and illuminates therapeutic openings to target the expression of oncogenes. Kovalski et al. perform a genome-wide CRISPRi screen for selective MYC mRNA translation regulators and identify RBM42 as a ribosome-associated protein that modulates translation of MYC and an oncogenic mRNA programme required for pancreatic cancer growth.