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 Breese & 8 others Marco 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

22 Citations (Scopus)

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

Fingerprint

Medulloblastoma
5' Untranslated Regions
RNA
DEAD-box RNA Helicases
Cerebellar Neoplasms
Ribosomal RNA
Protein Biosynthesis
Chromatin
Messenger RNA
Mutation
Genes
Neoplasms
arsenite

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress. / Oh, Sekyung; Flynn, Ryan A.; Floor, Stephen N.; Purzner, James; Martin, Lance; Do, Brian T.; Schubert, Simone; Vaka, Dedeepya; Morrissy, Sorana; Li, Yisu; Kool, Marcel; Hovestadt, Volker; Jones, David T.W.; Northcott, Paul A.; Risch, Thomas; Warnatz, Hans Jörg; Yaspo, Marie Laure; Adams, Christopher M.; Leib, Ryan D.; Breese, Marcus; Marra, Marco A.; Malkin, David; Lichter, Peter; Doudna, Jennifer A.; Pfister, Stefan M.; Taylor, Michael D.; Chang, Howard Y.; Cho, Yoon-Jae.

In: Oncotarget, Vol. 7, No. 19, 10.05.2016, p. 28169-28182.

Research output: Contribution to journalArticle

Oh, S, Flynn, RA, Floor, SN, Purzner, J, Martin, L, Do, BT, Schubert, S, Vaka, D, Morrissy, S, Li, Y, Kool, M, Hovestadt, V, Jones, DTW, Northcott, PA, Risch, T, Warnatz, HJ, Yaspo, ML, Adams, CM, Leib, RD, Breese, M, Marra, MA, Malkin, D, Lichter, P, Doudna, JA, Pfister, SM, Taylor, MD, Chang, HY & Cho, Y-J 2016, 'Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress', Oncotarget, vol. 7, no. 19, pp. 28169-28182. https://doi.org/10.18632/oncotarget.8612
Oh, Sekyung ; Flynn, Ryan A. ; Floor, Stephen N. ; Purzner, James ; Martin, Lance ; Do, Brian T. ; Schubert, Simone ; Vaka, Dedeepya ; Morrissy, Sorana ; Li, Yisu ; Kool, Marcel ; Hovestadt, Volker ; Jones, David T.W. ; Northcott, Paul A. ; Risch, Thomas ; Warnatz, Hans Jörg ; Yaspo, Marie Laure ; Adams, Christopher M. ; Leib, Ryan D. ; Breese, Marcus ; Marra, Marco A. ; Malkin, David ; Lichter, Peter ; Doudna, Jennifer A. ; Pfister, Stefan M. ; Taylor, Michael D. ; Chang, Howard Y. ; Cho, Yoon-Jae. / Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress. In: Oncotarget. 2016 ; Vol. 7, No. 19. pp. 28169-28182.
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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.",
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AU - Oh, Sekyung

AU - Flynn, Ryan A.

AU - Floor, Stephen N.

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AU - Martin, Lance

AU - Do, Brian T.

AU - Schubert, Simone

AU - Vaka, Dedeepya

AU - Morrissy, Sorana

AU - Li, Yisu

AU - Kool, Marcel

AU - Hovestadt, Volker

AU - Jones, David T.W.

AU - Northcott, Paul A.

AU - Risch, Thomas

AU - Warnatz, Hans Jörg

AU - Yaspo, Marie Laure

AU - Adams, Christopher M.

AU - Leib, Ryan D.

AU - Breese, Marcus

AU - Marra, Marco A.

AU - Malkin, David

AU - Lichter, Peter

AU - Doudna, Jennifer A.

AU - Pfister, Stefan M.

AU - Taylor, Michael D.

AU - Chang, Howard Y.

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