biostudies-literatureUnknownHofman DABritish Heart FoundationNCI NIH HHSA 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. 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 step-wise approach to employ multiple CRISPR-Cas9 screens to elucidate functional non-canonical ORFs implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream open reading frames (uORFs) exhibited selective functionality independent of the main coding sequence. One of these, ASNSD1-uORF or ASDURF, was upregulated, associated with the MYC family oncogenbioRxiv : the preprint server for biology2023.05.04.539399https://www.ebi.ac.uk/biostudies/studies/S-EPMC10187264biostudies-literatureTranslation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma.PMC10187264SP/19/1/34461R35 CA242457K08 CA263552Brown AGoodale ALigon KLHofman DACondurat ALRoot DEvan Dinter JTClauser KRPhoenix TNPrensner JRvan Heesch SWang LBandopadhayay PAbid THubner NMurugesan RRuiz-Orera JZhou KNEngels SAGvan der Lugt JYannuzzi IVogelzang JRoth JAGolub TRfalseTranslation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma.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. 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 step-wise approach to employ multiple CRISPR-Cas9 screens to elucidate functional non-canonical ORFs implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream open reading frames (uORFs) exhibited selective functionality independent of the main coding sequence. One of these, ASNSD1-uORF or ASDURF, was upregulated, associated with the MYC family oncogen2023-01-01T00:00:00Z2023 May2026-04-08T13:54:51.172Z2025-02-19T04:20:44.244ZS-EPMC101872643720549210.1101/2023.05.04.539399