The helicase Ded1p controls use of near-cognate translation initiation codons in 5′ UTRs
The conserved and essential DEAD-box RNA helicase Ded1p from yeast and its mammalian orthologue DDX3 are critical for the initiation of translation 1 . Mutations in DDX3 are linked to tumorigenesis 2-4 and intellectual disability 5, and the enzyme is targeted by a range of viruses 6 . How Ded1p and...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2020
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| Online Access: | https://hdl.handle.net/1721.1/125996 |
| _version_ | 1811090103586521088 |
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| author | Guenther, Ulf-Peter Weinberg, David E. Zubradt, Meghan M. Tedeschi, Frank A. Stawicki, Brittany N. Zagore, Leah L. Brar, Gloria A. Licatalosi, Donny D. Bartel, David Weissman, Jonathan S. Jankowsky, Eckhard |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Guenther, Ulf-Peter Weinberg, David E. Zubradt, Meghan M. Tedeschi, Frank A. Stawicki, Brittany N. Zagore, Leah L. Brar, Gloria A. Licatalosi, Donny D. Bartel, David Weissman, Jonathan S. Jankowsky, Eckhard |
| author_sort | Guenther, Ulf-Peter |
| collection | MIT |
| description | The conserved and essential DEAD-box RNA helicase Ded1p from yeast and its mammalian orthologue DDX3 are critical for the initiation of translation 1 . Mutations in DDX3 are linked to tumorigenesis 2-4 and intellectual disability 5, and the enzyme is targeted by a range of viruses 6 . How Ded1p and its orthologues engage RNAs during the initiation of translation is unknown. Here we show, by integrating transcriptome-wide analyses of translation, RNA structure and Ded1p-RNA binding, that the effects of Ded1p on the initiation of translation are connected to near-cognate initiation codons in 5′ untranslated regions. Ded1p associates with the translation pre-initiation complex at the mRNA entry channel and repressing the activity of Ded1p leads to the accumulation of RNA structure in 5′ untranslated regions, the initiation of translation from near-cognate start codons immediately upstream of these structures and decreased protein synthesis from the corresponding main open reading frames. The data reveal a program for the regulation of translation that links Ded1p, the activation of near-cognate start codons and mRNA structure. This program has a role in meiosis, in which a marked decrease in the levels of Ded1p is accompanied by the activation of the alternative translation initiation sites that are seen when the activity of Ded1p is repressed. Our observations indicate that Ded1p affects translation initiation by controlling the use of near-cognate initiation codons that are proximal to mRNA structure in 5′ untranslated regions. |
| first_indexed | 2024-09-23T14:33:32Z |
| format | Article |
| id | mit-1721.1/125996 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T14:33:32Z |
| publishDate | 2020 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1259962022-10-01T21:43:17Z The helicase Ded1p controls use of near-cognate translation initiation codons in 5′ UTRs Guenther, Ulf-Peter Weinberg, David E. Zubradt, Meghan M. Tedeschi, Frank A. Stawicki, Brittany N. Zagore, Leah L. Brar, Gloria A. Licatalosi, Donny D. Bartel, David Weissman, Jonathan S. Jankowsky, Eckhard Massachusetts Institute of Technology. Department of Biology The conserved and essential DEAD-box RNA helicase Ded1p from yeast and its mammalian orthologue DDX3 are critical for the initiation of translation 1 . Mutations in DDX3 are linked to tumorigenesis 2-4 and intellectual disability 5, and the enzyme is targeted by a range of viruses 6 . How Ded1p and its orthologues engage RNAs during the initiation of translation is unknown. Here we show, by integrating transcriptome-wide analyses of translation, RNA structure and Ded1p-RNA binding, that the effects of Ded1p on the initiation of translation are connected to near-cognate initiation codons in 5′ untranslated regions. Ded1p associates with the translation pre-initiation complex at the mRNA entry channel and repressing the activity of Ded1p leads to the accumulation of RNA structure in 5′ untranslated regions, the initiation of translation from near-cognate start codons immediately upstream of these structures and decreased protein synthesis from the corresponding main open reading frames. The data reveal a program for the regulation of translation that links Ded1p, the activation of near-cognate start codons and mRNA structure. This program has a role in meiosis, in which a marked decrease in the levels of Ded1p is accompanied by the activation of the alternative translation initiation sites that are seen when the activity of Ded1p is repressed. Our observations indicate that Ded1p affects translation initiation by controlling the use of near-cognate initiation codons that are proximal to mRNA structure in 5′ untranslated regions. 2020-06-26T14:52:38Z 2020-06-26T14:52:38Z 2018-06 2017-01 2019-11-26T18:26:57Z Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 https://hdl.handle.net/1721.1/125996 Guenther, Ulf-Peter et al. "The helicase Ded1p controls use of near-cognate translation initiation codons in 5′ UTRs." Nature 559, 7712 (June 2018): 130–134. © 2018 Macmillan Publishers Ltd., part of Springer Nature en http://dx.doi.org/10.1038/s41586-018-0258-0 Nature Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Guenther, Ulf-Peter Weinberg, David E. Zubradt, Meghan M. Tedeschi, Frank A. Stawicki, Brittany N. Zagore, Leah L. Brar, Gloria A. Licatalosi, Donny D. Bartel, David Weissman, Jonathan S. Jankowsky, Eckhard The helicase Ded1p controls use of near-cognate translation initiation codons in 5′ UTRs |
| title | The helicase Ded1p controls use of near-cognate translation initiation codons in 5′ UTRs |
| title_full | The helicase Ded1p controls use of near-cognate translation initiation codons in 5′ UTRs |
| title_fullStr | The helicase Ded1p controls use of near-cognate translation initiation codons in 5′ UTRs |
| title_full_unstemmed | The helicase Ded1p controls use of near-cognate translation initiation codons in 5′ UTRs |
| title_short | The helicase Ded1p controls use of near-cognate translation initiation codons in 5′ UTRs |
| title_sort | helicase ded1p controls use of near cognate translation initiation codons in 5 utrs |
| url | https://hdl.handle.net/1721.1/125996 |
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