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Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma

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Item Type:Article
Title:Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma
Creators Name:Hofman, D.A. and Ruiz-Orera, J. and Yannuzzi, I. and Murugesan, R. and Brown, A. and Clauser, K.R. and Condurat, A.L. and van Dinter, J.T. and Engels, S.A.G. and Goodale, A. and van der Lugt, J. and Abid, T. and Wang, L. and Zhou, K.N. and Vogelzang, J. and Ligon, K.L. and Phoenix, T.N. and Roth, J.A. and Root, D.E and Hubner, N. and Golub, T.R. and Bandopadhayay, P. and van Heesch, S. and Prensner, J.R.
Abstract:A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames (ORFs). To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a stepwise approach using multiple CRISPR-Cas9 screens to elucidate non-canonical ORFs and putative microproteins implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream ORFs (uORFs) exhibited selective functionality independent of main coding sequences. A microprotein encoded by one of these ORFs, ASNSD1-uORF or ASDURF, was upregulated, associated with MYC-family oncogenes, and promoted medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future studies seeking to define new cancer targets.
Keywords:Cancer, Gene Dependency, CRISPR, Medulloblastoma, Non-Canonical ORFs, Ribo-Seq, Translational Regulation, lncRNAs, uORF
Source:Molecular Cell
ISSN:1097-2765
Publisher:Cell Press
Volume:84
Number:2
Page Range:261-276.e18
Date:18 January 2024
Official Publication:https://doi.org/10.1016/j.molcel.2023.12.003
PubMed:View item in PubMed

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