Functional screen for mediators of onco-mRNA translation specificity

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Oncogenic protein levels are critical for cancer cell adaptation and survival.
• Translational control mechanisms and key regulatory factors for oncogenes remain largely unknown.
• The Myc oncogene is a key driver in pancreatic ductal adenocarcinoma (PDAC).

Purpose of the Study:

• To identify factors regulating selective translation of the Myc oncogene in PDAC.
• To investigate the role of RNA binding proteins (RBPs) in Myc translation.
• To explore RBM42 as a potential therapeutic target in PDAC.

Main Methods:

• Genome-wide CRISPRi screen in PDAC cells.
• Functional assays including polysome sequencing and CLIP-seq.
• IP-mass spectrometry, DMS-Seq, and mutagenesis analysis.
• In vivo xenograft mouse models and analysis of PDAC patient samples.

Main Results:

• Identified RBM42 as a key activator of selective MYC translation via its 5' untranslated region (5'UTR).
• RBM42 selectively regulates translation of MYC, JUN, and EGFR, and is a novel ribosome-associated protein (RAP).
• RBM42 remodels the MYC 5'UTR RNA structure, promoting translation initiation and is essential for PDAC cell growth and tumorigenesis.

Conclusions:

• RBM42 plays a critical role in PDAC pathogenesis by controlling oncogene translation.
• RBM42 expression correlates with Myc levels and poor survival in PDAC patients.
• Targeting RBM42 offers a novel therapeutic strategy for pancreatic cancer.