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

Damon A Hofman, Jorge Ruiz-Orera, Ian Yannuzzi, Rakesh Murugesan, Adam Brown, Karl R Clauser, Alexandra L Condurat, Jip T van Dinter, Sem A G Engels, Amy Goodale, Jasper van der Lugt, Tanaz Abid, Li Wang, Kevin N Zhou, Jayne Vogelzang, Keith L Ligon, Timothy N Phoenix, Jennifer A Roth, David E Root, Norbert HubnerTodd R Golub, Pratiti Bandopadhayay, Sebastiaan van Heesch, John R Prensner

Research output: Contribution to journalArticle


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 oncogenes, and was required for 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 cancer genomics studies seeking to define new cancer targets.

Original languageEnglish
Publication statusPublished - 6 May 2023


Dive into the research topics of 'Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma'. Together they form a unique fingerprint.

Cite this