Journal Article

DKFZ-2017-05355

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress.

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.DKFZ* ; Hovestadt, V.DKFZ* ; Jones, D.DKFZ* ; Northcott, P. A.DKFZ* ; Risch, T. ; Warnatz, H.-J. ; Yaspo, M.-L. ; Adams, C. M. ; Leib, R. D. ; Breese, M. ; Marra, M. A. ; Malkin, D. ; Lichter, P.DKFZ* ; Doudna, J. A. ; Pfister, S.DKFZ* ; Taylor, M. D. ; Chang, H. Y. ; Cho, Y.-J.

2016
Impact Journals LLC [S.l.]

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Please use a persistent id in citations: doi:10.18632/oncotarget.8612

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 DDX3s interactions with RNA remain unclear. Here, we show DDX3 collaborates extensively with the translation initiation machinery through direct binding to 5UTRs 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 DDX3s role in this process. Arsenite-induced stress shifts DDX3 binding from the 5UTR 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, medulloblastoma-associated 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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Contributing Institute(s):

1. Pädiatrische Neuroonkologie (B062)
2. Molekulare Genetik (B060)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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