Human medulloblastoma ASNSD1 uORF KO LC-MSMS

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. 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 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 open reading frames (uORFs) exhibited selective functionality independent of the main coding sequence. A microprotein encoded by one of these ORFs, 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 studies seeking to define new cancer targets.

INSTRUMENT(S): orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Malignant Cell, Cell Culture

DISEASE(S): Medulloblastoma Non-wnt/non-shh Group 3,Childhood Medulloblastoma

SUBMITTER: Damon Hofman  

LAB HEAD: John R. Prensner

PROVIDER: PXD046091 | Pride | 2024-01-03

REPOSITORIES: Pride