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

// Sekyung Oh 1, 2, * , Ryan A. Flynn 3, * , Stephen N. Floor 4 , James Purzner 5, 6 , Lance Martin 4 , Brian T. Do 4 , Simone Schubert 1 , Dedeepya Vaka 1 , Sorana Morrissy 7, 8 , Yisu Li 9 , Marcel Kool 10 , Volker Hovestadt 11 , David T.W. Jones 10 , Paul A. Northcott 10 , Thomas Risch 12 , Hans-Jörg Warnatz 12 , Marie-Laure Yaspo 12 , Christopher M. Adams 13 , Ryan D. Leib 13 , Marcus Breese 14 , Marco A. Marra 9 , David Malkin 15 , Peter Lichter 11 , Jennifer A. Doudna 4, 16, 17, 18 , Stefan M. Pfister 10 , Michael D. Taylor 7, 8, 9, 19 , Howard Y. Chang 3, 20, # , Yoon-Jae Cho 1, 2, 21, 22, # 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA 2 Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA 3 Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA 4 Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA 5 Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA 6 Department of Surgery, Division of Neurosurgery, University of Toronto, ON, Canada 7 Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada 8 Department of Surgery, Division of Neurosurgery and Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada 9 Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC Canada 10 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany 11 Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany 12 Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany 13 The Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University, Stanford, CA, USA 14 Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA 15 Cancer Genetic Program, The Hospital for Sick Children, Toronto, ON, Canada 16 Department of Chemistry, University of California, Berkeley, CA, USA 17 Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA 18 Howard Hughes Medical Institute, University of California, Berkeley, CA, USA 19 Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada 20 Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA 21 Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA 22 Knight 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: chyo@ohsu.edu Howard Y. Chang, email: howchang@stanford.edu 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 DDX3 R534H variant. Furthermore, despite the global repression of translation induced by arsenite, translation is preserved on select genes involved in chromatin organization in DDX3 R534H -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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