TY  - JOUR
AU  - Oh, Sekyung
AU  - Flynn, Ryan A
AU  - Floor, Stephen N
AU  - Purzner, James
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
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
AU  - Taylor, Michael D
AU  - Chang, Howard Y
AU  - Cho, Yoon-Jae
TI  - Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress.
JO  - OncoTarget
VL  - 7
IS  - 19
SN  - 1949-2553
CY  - [S.l.]
PB  - Impact Journals LLC
M1  - DKFZ-2017-05355
SP  - 28169 - 28182
PY  - 2016
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:27058758
C2  - pmc:PMC5053718
DO  - DOI:10.18632/oncotarget.8612
UR  - https://inrepo02.dkfz.de/record/130276
ER  -