Research Papers:
Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress
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Abstract
Sekyung Oh1,2,*, Ryan A. Flynn3,*, Stephen N. Floor4, James Purzner5,6, Lance Martin4, Brian T. Do4, Simone Schubert1, Dedeepya Vaka1, Sorana Morrissy7,8, Yisu Li9, Marcel Kool10, Volker Hovestadt11, David T.W. Jones10, Paul A. Northcott10, Thomas Risch12, Hans-Jörg Warnatz12, Marie-Laure Yaspo12, Christopher M. Adams13, Ryan D. Leib13, Marcus Breese14, Marco A. Marra9, David Malkin15, Peter Lichter11, Jennifer A. Doudna4,16,17,18, Stefan M. Pfister10, Michael D. Taylor7,8,9,19, Howard Y. Chang3,20,#, Yoon-Jae Cho1,2,21,22,#
1Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
2Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
3Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA
4Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
5Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA
6Department of Surgery, Division of Neurosurgery, University of Toronto, ON, Canada
7Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
8Department of Surgery, Division of Neurosurgery and Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
9Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC Canada
10Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
11Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
12Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany
13The Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University, Stanford, CA, USA
14Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA
15Cancer Genetic Program, The Hospital for Sick Children, Toronto, ON, Canada
16Department of Chemistry, University of California, Berkeley, CA, USA
17Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
18Howard Hughes Medical Institute, University of California, Berkeley, CA, USA
19Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada
20Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA
21Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA
22Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
*These authors contributed equally to this work
#These authors share co-senior authorship
Correspondence to:
Yoon-Jae Cho, email: [email protected]
Howard Y. Chang, email: [email protected]
Keywords: medulloblastoma, DDX3X, DDX3, RNA helicase, CLIP-seq
Received: March 17, 2016 Accepted: March 26, 2016 Published: April 05, 2016
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, 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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