Human oncoprotein 5MP suppresses general and repeat-associated non-AUG translation via eIF3 by a common mechanism

Singh, Chingakham Ranjit; Glineburg, M. Rebecca; Moore, Chelsea; Tani, Naoki; Jaiswal, Rahul; Zou, Ye; Aube, Eric; Gillaspie, Sarah; Thornton, Mackenzie; Cecil, Ariana; Hilgers, Madelyn; Takasu, Azuma; Asano, Izumi; Asano, Masayo; Escalante, Carlos; Nakamura, Akira; Todd, Peter K.; Asano, Katsura

doi:10.1016/j.celrep.2021.109376

Cited by 24 publications

(29 citation statements)

References 71 publications

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“…Long repetitive sequences have been shown to stimulate translation initiation upstream; more details on the molecular processes and associated disease etiology can be found in several reviews dedicated to this topic [ 69 – 71 ]. However, it is important to note that during RAN translation, recognition of non-AUG codons seems to occur via the standard cap-dependent mechanism and involves canonical initiation factors and regulators [ 72 – 74 ].…”

Section: Introductionmentioning

confidence: 99%

Non-AUG translation initiation in mammals

et al. 2022

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Recent proteogenomic studies revealed extensive translation outside of annotated protein coding regions, such as non-coding RNAs and untranslated regions of mRNAs. This non-canonical translation is largely due to start codon plurality within the same RNA. This plurality is often due to the failure of some scanning ribosomes to recognize potential start codons leading to initiation downstream—a process termed leaky scanning. Codons other than AUG (non-AUG) are particularly leaky due to their inefficiency. Here we discuss our current understanding of non-AUG initiation. We argue for a near-ubiquitous role of non-AUG initiation in shaping the dynamic composition of mammalian proteomes.

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Section: Introductionmentioning

confidence: 99%

Non-AUG translation initiation in mammals

et al. 2022

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“…In conclusion, we showed that, except for AUG, Ψ in the second NUG codon base strongly enhances initiation through increased base pairing to the mismatched start codon, while 5mC in the first base of a CUG codon diminishes initiation in a context-dependent manner. While non-AUG translation is known to be regulated by trans-acting factors independently of the codon types ( 13 , 25 , 39 ), codon-specific regulation has not been reported. To our knowledge, this is the first report that shows that the chemical modification of near-cognate start codons can specifically alter initiation frequency and hence recode translation initiation.…”

Section: Discussionmentioning

confidence: 99%

Translational recoding by chemical modification of non-AUG start codon ribonucleotide bases

et al. 2022

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In contrast to prokaryotes wherein GUG and UUG are permissive start codons, initiation frequencies from non-AUG codons are generally low in eukaryotes, with CUG being considered as strongest. Here, we report that combined 5-cytosine methylation (5mC) and pseudouridylation (Ψ) of near-cognate non-AUG start codons convert GUG and UUG initiation strongly favored over CUG initiation in eukaryotic translation under a certain context. This prokaryotic-like preference is attributed to enhanced NUG initiation by Ψ in the second base and reduced CUG initiation by 5mC in the first base. Molecular dynamics simulation analysis of tRNA i Met anticodon base pairing to the modified codons demonstrates that Ψ universally raises the affinity of codon:anticodon pairing within the ribosomal preinitiation complex through partially mitigating discrimination against non-AUG codons imposed by eukaryotic initiation factor 1. We propose that translational control by chemical modifications of start codon bases can offer a new layer of proteome diversity regulation and therapeutic mRNA technology.

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“…(a-c) arrow with a dotted line, change in place and/or in time; solid lines show induction or inhibition of certain processes translation but its role in RAN translation regulation is yet to be defined (Cate, 2017;Hashem et al, 2013). Further studies demonstrating the role of eiF3 in both canonical and RAN translation initiation on CGG exp indicated that human oncoprotein eIF5-mimic (5MP) displaces eIF5 through eIF3c subunit within the PIC and thus affects both modes of translation via increasing the accuracy of translation initiation (Singh et al, 2021;Tang et al, 2017). In addition, it was shown that overexpression of Drosophila 5MP homolog in FXTAS flies reduced RAN peptides-mediated toxicity (Singh et al, 2021).…”

Section: Ran Translationmentioning

confidence: 99%

“…Further studies demonstrating the role of eiF3 in both canonical and RAN translation initiation on CGG exp indicated that human oncoprotein eIF5-mimic (5MP) displaces eIF5 through eIF3c subunit within the PIC and thus affects both modes of translation via increasing the accuracy of translation initiation (Singh et al, 2021;Tang et al, 2017). In addition, it was shown that overexpression of Drosophila 5MP homolog in FXTAS flies reduced RAN peptides-mediated toxicity (Singh et al, 2021). Recently, Sonobe et al (2021) developed a new C. elegans model of C9-ALS/FTD.…”

Section: Ran Translationmentioning

confidence: 99%

Partners in crime: Proteins implicated in RNA repeat expansion diseases

et al. 2022

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Short tandem repeats are repetitive nucleotide sequences robustly distributed in the human genome. Their expansion underlies the pathogenesis of multiple neurological disorders, including Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, fragile X-associated tremor/ ataxia syndrome, and myotonic dystrophies, known as repeat expansion disorders (REDs). Several molecular pathomechanisms associated with toxic RNA containing expanded repeats (RNA exp ) are shared among REDs and contribute to disease progression, however, detailed mechanistic insight into those processes is limited. To deepen our understanding of the interplay between toxic RNA exp molecules and multiple protein partners, in this review, we discuss the roles of selected RNA-binding proteins (RBPs) that interact with RNA exp and thus act as "partners in crime" in the progression of REDs. We gather current findings concerning RBPs involved at different stages of the RNA exp life cycle, such as transcription, splicing, transport, and AUG-independent translation of expanded repeats. We argue that the activity of selected RBPs can be unique or common among REDs depending on the expanded repeat type. We also present proteins that are functionally depleted due to sequestration on RNA exp within nuclear foci and those which participate in RNA exp -dependent innate immunity activation.Abbreviations: 3 0 UTR/5 0 UTR, 3 0 /5 0 untranslated regions; AS, alternative splicing; ASO, antisense oligonucleotide; C9-ALS/FTD, C9orf72-linked amyotrophic lateral sclerosis and frontotemporal dementia; CAG exp , expanded CAG repeats; CCUG exp , expanded CCUG repeats; CGG exp , expanded CGG repeats; CTG exp , expanded CTG repeats; CUG exp , expanded CUG repeats;

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Human oncoprotein 5MP suppresses general and repeat-associated non-AUG translation via eIF3 by a common mechanism

Cited by 24 publications

References 71 publications

Non-AUG translation initiation in mammals

Non-AUG translation initiation in mammals

Translational recoding by chemical modification of non-AUG start codon ribonucleotide bases

Partners in crime: Proteins implicated in RNA repeat expansion diseases

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