eIF1A residues implicated in cancer stabilize translation preinitiation complexes and favor suboptimal initiation sites in yeast

Martín-Marcos, Pilar; Zhou, Fujun; Karunasiri, Charm; Zhang, Fan; Dong, Jinsheng; Nanda, Jagpreet S.; Kulkarni, Shardul D.; Sen, Neelam Dabas; Tamame, Mercedes; Zeschnigk, Michael; Lorsch, Jon R.; Hinnebusch, Alan G.

doi:10.7554/elife.31250

Cited by 47 publications

(48 citation statements)

References 67 publications

(118 reference statements)

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“…EIF1AX mutations have been presumed to result in a change-of-function or gain-offunction because of their predilection for specific substitutions in the N-and C-terminal tails. However, functional insights so far have been primarily confined to how EIF1AX mutants alter usage of initiation codons with varying contexts in yeast (25,29). In uveal melanomas, EIF1AX-NTT mutants are associated with relatively indolent disease.…”

Section: Discussionmentioning

confidence: 99%

“…When TC availability is limited, the ribosome fails to reassemble at uORF2 and instead reinitiates translation at the canonical ATF4 start codon (28). As EIF1AX is known to affect the fidelity of start codon selection (25,29), we tested whether EIF1AX-splice preferentially translates ATF4 by altering selectivity toward the two upstream ( −3 ACCAUG/ −3 GCCAUG) and the main ( −3 AACAUG) ATF4 start codons. For this, we engineered reporter constructs in which the firefly luciferase protein was under control of the different ATF4 translation initiation contexts (Kozak + start codons).…”

Section: Increased Global Protein Synthesis By Eif1ax-splice Is Mediamentioning

confidence: 99%

“…EIF1AX mutations are always heterozygous, suggesting that full occupancy of PICs by mutant EIF1AX would be detrimental to viability. Structure-function studies in yeast revealed that mutating any of the NTT residues between 7 and 16 AAs were lethal and resulted in leaky scanning of the initiation AUG codon (23,24), and discriminated against AUGs with poor context (25). By contrast, CTT mutants enhanced noncanonical AUG initiations.…”

Section: Introductionmentioning

confidence: 99%

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EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC

et al. 2019

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Translation initiation is orchestrated by the cap binding and 43S preinitiation complexes (PIC). Eukaryotic initiation factor 1A (EIF1A) is essential for recruitment of the ternary complex and for assembling the 43S PIC. Recurrent EIF1AX mutations in papillary thyroid cancers are mutually exclusive with other drivers, including RAS . EIF1AX mutations are enriched in advanced thyroid cancers, where they display a striking co-occurrence with RAS , which cooperates to induce tumorigenesis in mice and isogenic cell lines. The C-terminal EIF1AX-A113splice mutation is the most prevalent in advanced thyroid cancer. EIF1AX-A113splice variants stabilize the PIC and induce ATF4, a sensor of cellular stress, which is co-opted to suppress EIF2α phosphorylation, enabling a general increase in protein synthesis. RAS stabilizes c-MYC, an effect augmented by EIF1AX-A113splice. ATF4 and c-MYC induce expression of amino acid transporters and enhance sensitivity of mTOR to amino acid supply. These mutually reinforcing events generate therapeutic vulnerabilities to MEK, BRD4, and mTOR kinase inhibitors. SIGNIFICANCE:Mutations of EIF1AX, a component of the translation PIC, co-occur with RAS in advanced thyroid cancers and promote tumorigenesis. EIF1AX-A113splice drives an ATF4-induced dephosphorylation of EIF2α, resulting in increased protein synthesis. ATF4 also cooperates with c-MYC to sensitize mTOR to amino acid supply, thus generating vulnerability to mTOR kinase inhibitors.EIF1AX is an essential subunit of the translation PIC (10, 12). We performed coimmunoprecipitation (co-IP) experiments to probe for possible aberrant interactions of EIF1AX mutants with components of the TC and the PIC. IP of Research.on July 10, 2020.

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Section: Discussionmentioning

confidence: 99%

Section: Increased Global Protein Synthesis By Eif1ax-splice Is Mediamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC

et al. 2019

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“…eIF1A Promotes Translation of Cell Cycle Genes Molecular and Cellular Biology initiation site selection (25). This finding can be explained by a higher degree of redundancy of this activity among mammalian eIFs as well as the fact that both eIF1 and eIF1A are each encoded by at least two genes.…”

Section: Discussionmentioning

confidence: 99%

Cancer-Associated Eukaryotic Translation Initiation Factor 1A Mutants Impair Rps3 and Rps10 Binding and Enhance Scanning of Cell Cycle Genes

Sehrawat

Koning

Ashkenazi

et al. 2019

Molecular and Cellular Biology

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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.

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“…HIST1H3B, SMARCB1 and SETBP1 are involved in epigenetic regulation and their mutations can alter gene expression patterns [44,45] . Mutations of EIF1AX and RPS15 are likely to perturb translation events [46,47] . However, SRSF2, which is responsible for orchestrating splicing events, can also have a global influence on cellular states [48] .…”

Section: Discussionmentioning

confidence: 99%

Ancient evolutionary origin of intrinsically disordered cancer risk regions

Pajkos

Zeke

Dosztányi

2020

Preprint

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Cancer is a heterogeneous genetic disease that alters the proper functioning of proteins involved in key regulatory processes such as cell cycle, DNA repair, survival or apoptosis. Mutations often accumulate in hot-spots regions, highlighting critical functional modules within these proteins that need to be altered, amplified or abolished for tumor formation. Recent evidence suggests that these mutational hotspots can not only correspond to globular domains but also to intrinsically disordered regions (IDRs), which play a significant role in a subset of cancer types. IDRs have distinct functional properties that originate from their inherent flexibility. Generally, they correspond to more recent evolutionary inventions and show larger sequence variations across species. In this work we analyzed the evolutionary origin of disordered regions that are specifically targeted in cancer. Surprisingly, the majority of these disordered cancer risk regions showed remarkable conservation with ancient evolutionary origin, stemming from the earliest multicellular animals or even beyond. Nevertheless, we encountered several examples, where the mutated region emerged at a later stage compared to the origin of the gene family. We also showed the cancer risk regions become quickly fixated after their emergence, but evolution continues to tinker with their genes with novel regulatory elements introduced even at the level of humans. Our concise analysis provides a much clearer picture of the emergence of key regulatory elements in proteins and highlights the importance of taking into account the modular organisation of proteins for the analyses of evolutionary origin.

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eIF1A residues implicated in cancer stabilize translation preinitiation complexes and favor suboptimal initiation sites in yeast

Cited by 47 publications

References 67 publications

EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC

EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC

Cancer-Associated Eukaryotic Translation Initiation Factor 1A Mutants Impair Rps3 and Rps10 Binding and Enhance Scanning of Cell Cycle Genes

Ancient evolutionary origin of intrinsically disordered cancer risk regions

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