title: Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress.
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.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.|Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Sekyung
authors.initials: S
authors.lastname: Oh
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Flynn
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Floor
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.|Department of Surgery, Division of Neurosurgery, University of Toronto, ON, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Purzner
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
authors.forename: Lance
authors.initials: L
authors.lastname: Martin
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Do
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Schubert
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Dedeepya
authors.initials: D
authors.lastname: Vaka
authors.affiliation: Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.|Department of Surgery, Division of Neurosurgery and Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Sorana
authors.initials: S
authors.lastname: Morrissy
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC Canada.
authors.forename: Yisu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Risch
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Warnatz
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Yaspo
authors.affiliation: The Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University, Stanford, CA, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Adams
authors.affiliation: The Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University, Stanford, CA, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Leib
authors.affiliation: Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Breese
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC Canada.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: Cancer Genetic Program, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.|Department of Chemistry, University of California, Berkeley, CA, USA.|Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.|Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Doudna
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.|Department of Surgery, Division of Neurosurgery and Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.|Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.|Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.|Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.|Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
mesh_terms: D002528:Cerebellar Neoplasms / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics*; D059467:Transcriptome
chemical_list: C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases
keywords: CLIP-seq; DDX3; DDX3X; RNA helicase; medulloblastoma