Journal
ONCOTARGET
Volume 7, Issue 19, Pages 28169-28182Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.8612
Keywords
medulloblastoma; DDX3X; DDX3; RNA helicase; CLIP-seq
Categories
Funding
- St. Baldrick's Foundation Scholar Award
- Beirne Faculty Scholar Endowment
- NIH [U01-CA176287]
- Stanford Center for Children's Brain Tumors
- Stanford University Mass Spectrometry Seed Grant
- Center for RNA Systems Biology [5P50GM102706]
- Genome Canada
- Genome BC
- Terry Fox Research Institute
- Ontario Institute for Cancer Research
- Pediatric Oncology Group Ontario
- Family of Kathleen Lorette
- Clark H. Smith Brain Tumour Centre
- Montreal Children's Hospital Foundation
- Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre
- Cancer Genetics Program
- Garron Family Cancer Centre
- German Cancer Aid [S.M.P.109252]
- German Federal Ministry of Education and Research [01KU1201A, 0315416C, 01GS0883]
- B.R.A.I.N. Child
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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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