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.