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:10.2139/ssrn.3783404

Cited by 5 publications

(13 citation statements)

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“…Our study also encountered some technical limitations. In line with previous observations on FXTAS, RAN translation of the XDP‐specific (AGAGGG) n repeats was highly inefficient, showing <1% efficiency relative to canonical AUG translation 31 . Furthermore, the near‐cognate AGG initiation codon, which repeatedly occurs within the (AGAGGG) n repeat motif, did not show significantly higher expression levels than the GGG‐nLuc‐3xFLAG negative control in a prior investigation 32 .…”

Section: Discussionsupporting

confidence: 89%

“…These limitations precluded us from directly detecting the nLuc tag via luciferase assays, immunofluorescence, and immunocytochemistry. RAN translation is a highly inefficient process relative to canonical AUG translation, and the slow accumulation of toxic proteins has been linked to the age‐associated penetrance of these diseases 17,31 . However, cellular stress triggered by protein misfolding can promote RAN translation while suppressing global AUG translation 18,33 .…”

Section: Discussionmentioning

confidence: 99%

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Repeat‐Associated Non‐AUG Translation of AGAGGG Repeats that Cause X‐Linked Dystonia‐Parkinsonism

et al. 2022

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Background: X-linked dystoniaparkinsonism (XDP) is a neurodegenerative disorder caused by the intronic insertion of a SINE-VNTR-Alu (SVA) retrotransposon carrying an (AGAGGG) n repeat expansion in the TAF1 gene. The molecular mechanisms by which this mutation causes neurodegeneration remain elusive. Objectives: We investigated whether (AGAGGG) n repeats undergo repeat-associated non-AUG (RAN) translation, a pathogenic mechanism common among repeat expansion diseases. Methods: XDP-specific RAN translation reporter plasmids were generated, transfected in HEK293 cells, and putative dipeptide repeat proteins (DPRs) were detected by Western blotting. Immunocytochemistry was performed in COS-7 cells to determine the subcellular localization of one DPR. Results: We detected putative DPRs from two reading frames, supporting the translation of poly-(Glu-Gly) and poly-(Arg-Glu) species. XDP RAN translation initiates within the (AGAGGG) n sequence and poly-(Glu-Gly) DPRs formed nuclear inclusions in transfected cells. Conclusions: In summary, our work provides the first in-vitro proof of principle that the XDP-linked (AGAGGG) n repeat expansions can undergo RAN translation.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Repeat‐Associated Non‐AUG Translation of AGAGGG Repeats that Cause X‐Linked Dystonia‐Parkinsonism

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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“…The eIF3F acts as a non‐core component of eiF3 complex, which is known to regulate canonical and internal ribosome entry site (IRES)‐dependent 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 .…”

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 5 publications

References 0 publications

Repeat‐Associated Non‐AUG Translation of AGAGGG Repeats that Cause X‐Linked Dystonia‐Parkinsonism

Repeat‐Associated Non‐AUG Translation of AGAGGG Repeats that Cause X‐Linked Dystonia‐Parkinsonism

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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