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<p>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 <i>MYC</i> 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 <i>MYC</i> and a precise suite of pro-oncogenic transcripts, including <i>JUN</i> and <i>EGFR</i>. Mechanistically, we find that RBM42 binds and remodels the <i>MYC</i> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年2月4日

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  • Joanna R. Kovalski,
  • Goksu Sarioglu,
  • Vishvak Subramanyam,
  • Grace Hernandez,
  • Gilles Rademaker,
  • Juan A. Oses-Prieto,
  • Macey Slota,
  • Nimmy Mohan,
  • Kaylee Yiakis,
  • Isabelle Liu,
  • Kwun Wah Wen,
  • Grace E. Kim,
  • Sohit Miglani,
  • Alma L. Burlingame,
  • Hani Goodarzi,
  • Rushika M. Perera,
  • Davide Ruggero

摘要

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.