Journal article
Cancer-Associated Eukaryotic Translation Initiation Factor 1A Mutants Impair Rps3 and Rps10 Binding and Enhance Scanning of Cell Cycle Genes
- Abstract:
- Protein synthesis is linked to cell proliferation, and its deregulation contributes to cancer. Eukaryotic translation initiation factor 1A (eIF1A) plays a key role in scanning and AUG selection and differentially affects the translation of distinct mRNAs. Its unstructured N-terminal tail (NTT) is frequently mutated in several malignancies. Here we report that eIF1A is essential for cell proliferation and cell cycle progression. Ribosome profiling of eIF1A knockdown cells revealed a substantial enrichment of cell cycle mRNAs among the downregulated genes, which are predominantly characterized by a lengthy 5' untranslated region (UTR). Conversely, eIF1A depletion caused a broad stimulation of 5' UTR initiation at a near cognate AUG, unveiling a prominent role of eIF1A in suppressing 5' UTR translation. In addition, the AUG context-dependent autoregulation of eIF1 was disrupted by eIF1A depletion, suggesting their cooperation in AUG context discrimination and scanning. Importantly, cancer-associated eIF1A NTT mutants augmented the eIF1A positive effect on a long 5' UTR, while they hardly affected AUG selection. Mechanistically, these mutations diminished the eIF1A interaction with Rps3 and Rps10 implicated in scanning arrest. Our findings suggest that the reduced binding of eIF1A NTT mutants to the ribosome retains its open state and facilitates scanning of long 5' UTR-containing cell cycle genes.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Accepted manuscript, pdf, 1.8MB, Terms of use)
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- Publisher copy:
- 10.1128/MCB.00441-18
Authors
- Publisher:
- American Society for Microbiology
- Journal:
- Molecular and Cellular Biology More from this journal
- Volume:
- 39
- Issue:
- 3
- Article number:
- e00441-18
- Publication date:
- 2019-01-16
- Acceptance date:
- 2018-10-31
- DOI:
- EISSN:
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1098-5549
- ISSN:
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0270-7306
- Pmid:
-
30420357
- Language:
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English
- Keywords:
- Pubs id:
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pubs:944171
- UUID:
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uuid:dd1318f8-5cf0-4e57-89e2-66f7495c8d88
- Local pid:
-
pubs:944171
- Source identifiers:
-
944171
- Deposit date:
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2019-09-18
- ARK identifier:
Terms of use
- Copyright date:
- 2019
- Notes:
- Copyright © 2019 American Society for Microbiology. This is the accepted manuscript version of the article. The final version is available online from the American Society for Microbiology at: 10.1128/MCB.00441-18
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