Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress

Sekyung Oh, Ryan A. Flynn, Stephen N. Floor, James Purzner, Lance Martin, Brian T. Do, Simone Schubert, Dedeepya Vaka, Sorana Morrissy, Yisu Li, Marcel Kool, Volker Hovestadt, David T.W. Jones, Paul A. Northcott, Thomas Risch, Hans Jörg Warnatz, Marie Laure Yaspo, Christopher M. Adams, Ryan D. Leib, Marcus BreeseMarco A. Marra, David Malkin, Peter Lichter, Jennifer A. Doudna, Stefan M. Pfister, Michael D. Taylor, Howard Y. Chang, Yoon Jae Cho

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

DDX3X encodes a DEAD-box family RNA helicase (DDX3) commonly mutated in medulloblastoma, a highly aggressive cerebellar tumor affecting both children and adults. Despite being implicated in several facets of RNA metabolism, the nature and scope of DDX3's interactions with RNA remain unclear. Here, we show DDX3 collaborates extensively with the translation initiation machinery through direct binding to 5'UTRs of nearly all coding RNAs, specific sites on the 18S rRNA, and multiple components of the translation initiation complex. Impairment of translation initiation is also evident in primary medulloblastomas harboring mutations in DDX3X, further highlighting DDX3's role in this process. Arsenite-induced stress shifts DDX3 binding from the 5'UTR into the coding region of mRNAs concomitant with a general reduction of translation, and both the shift of DDX3 on mRNA and decreased translation are blunted by expression of a catalytically-impaired, medulloblastomaassociated DDX3R534H variant. Furthermore, despite the global repression of translation induced by arsenite, translation is preserved on select genes involved in chromatin organization in DDX3R534H-expressing cells. Thus, DDX3 interacts extensively with RNA and ribosomal machinery to help remodel the translation landscape in response to stress, while cancer-related DDX3 variants adapt this response to selectively preserve translation.

Original languageEnglish (US)
Pages (from-to)28169-28182
Number of pages14
JournalOncotarget
Volume7
Issue number19
DOIs
StatePublished - May 10 2016

Keywords

  • CLIP-seq
  • DDX3
  • DDX3X
  • Medulloblastoma
  • RNA helicase

ASJC Scopus subject areas

  • Oncology

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    Oh, S., Flynn, R. A., Floor, S. N., Purzner, J., Martin, L., Do, B. T., Schubert, S., Vaka, D., Morrissy, S., Li, Y., Kool, M., Hovestadt, V., Jones, D. T. W., Northcott, P. A., Risch, T., Warnatz, H. J., Yaspo, M. L., Adams, C. M., Leib, R. D., ... Cho, Y. J. (2016). Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress. Oncotarget, 7(19), 28169-28182. https://doi.org/10.18632/oncotarget.8612