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

Sekyung Oh1,2, Ryan A Flynn3, Stephen N Floor4

  • 1Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Oncotarget
|April 9, 2016
PubMed

Insights

The DEAD-box helicase DDX3X protein binds RNA and translation machinery, impacting medulloblastoma. Cancer-associated variants alter stress responses, selectively preserving translation of key genes.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • DDX3X mutations are common in medulloblastoma.
  • The precise role of DDX3X in RNA metabolism and translation is unclear.
  • Understanding DDX3X function is crucial for medulloblastoma research.

Purpose of the Study:

  • To elucidate the RNA-binding and functional interactions of DDX3X.
  • To investigate DDX3X's role in translation initiation and stress response.
  • To analyze the impact of medulloblastoma-associated DDX3X variants on cellular processes.

Main Methods:

  • RNA immunoprecipitation (RIP) followed by sequencing.
  • Analysis of translation initiation complex components.
  • Characterization of DDX3X variants (DDX3R534H) in cellular models.
  • Assessment of mRNA translation under stress conditions (arsenite).

Main Results:

  • DDX3X directly binds 5'UTRs of coding RNAs, 18S rRNA, and translation initiation factors.
  • Medulloblastoma samples with DDX3X mutations show impaired translation initiation.
  • Arsenite stress causes DDX3X to shift binding from 5'UTR to coding regions, reducing global translation.
  • The DDX3R534H variant blunts this stress-induced shift and preserves translation of chromatin organization genes.

Conclusions:

  • DDX3X is a key regulator of translation initiation and the cellular stress response.
  • Medulloblastoma-associated DDX3X variants exhibit altered stress response mechanisms.
  • DDX3X variants can selectively maintain translation of specific gene sets under stress, potentially contributing to tumorigenesis.
Keywords:
CLIP-seqDDX3DDX3XRNA helicasemedulloblastoma

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