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

Oh, S., Flynn, R. A., Floor, S. N., Purzner, J., Martin, L., Do, B. T., et al. (2016). Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress. Oncotarget, 7(19), 28169-28182. doi:10.18632/oncotarget.8612.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-B7FB-7 Version Permalink: http://hdl.handle.net/21.11116/0000-0000-B7FC-6
Genre: Journal Article

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 Creators:
Oh, S., Author
Flynn, R. A., Author
Floor, S. N., Author
Purzner, J., Author
Martin, L., Author
Do, B. T., Author
Schubert, S., Author
Vaka, D., Author
Morrissy, S., Author
Li, Y., Author
Kool, M., Author
Hovestadt, V., Author
Jones, D. T., Author
Northcott, P. A., Author
Risch, T., Author
Warnatz, H. J.1, Author              
Yaspo, M. L.1, Author              
Adams, C. M., Author
Leib, R. D., Author
Breese, M., Author
Marra, M. A., AuthorMalkin, D., AuthorLichter, P., AuthorDoudna, J. A., AuthorPfister, S. M., AuthorTaylor, M. D., AuthorChang, H. Y., AuthorCho, Y. J., Author more..
Affiliations:
1Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2117287              

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Free keywords: Cerebellar Neoplasms/*genetics DEAD-box RNA Helicases/*genetics Gene Expression Regulation, Neoplastic/genetics HEK293 Cells Humans Medulloblastoma/*genetics Protein Biosynthesis/*genetics Stress, Physiological/*genetics Transcriptome CLIP-seq Ddx3 Ddx3x RNA helicase medulloblastoma
 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.

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Language(s): eng - English
 Dates: 2016-04-052016-05-10
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.18632/oncotarget.8612
ISSN: 1949-2553 (Electronic)
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Title: Oncotarget
Source Genre: Journal
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Pages: - Volume / Issue: 7 (19) Sequence Number: - Start / End Page: 28169 - 28182 Identifier: ISSN: 1949-2553
CoNE: https://pure.mpg.de/cone/journals/resource/1949-2553