Altered proteome in translation initiation fidelity defective eIF5G31R mutant causes oxidative stress and DNA damage

Ram, Anup Kumar; Mallik, Monalisha; Reddy, R. Rajendra; Suryawanshi, Amol Ratnakar; Alone, Pankaj V.

doi:10.1038/s41598-022-08857-y

Cited by 5 publications

(4 citation statements)

References 67 publications

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“…Previously, we made HIS4-LacZ reporter constructs having start codon either AUG or UUG with change in sequence context from −3 to −1 position, where AAA constitutes good, and UUU constitutes a poor sequence context. As per HIS4-LacZ reporter data, the eIF5 G31R mutation showed a ~2.6-fold decrease in UUG codon recognition efficacy when the UUG codon was in the poor sequence context (Ram et al 2022).…”

Section: Resultsmentioning

confidence: 79%

“…Previously, we made HIS4-LacZ reporter constructs having start codon either AUG or UUG with change 9 in sequence context from -3 to -1 position, where AAA constitutes good, and UUU constitutes a poor sequence context. As per HIS4-LacZ reporter data, the eIF5 G31R mutation showed a ~2.6-fold decrease in UUG codon recognition efficacy when the UUG codon was in the poor sequence context(Ram et al 2022). To further delineate the effect of the different nucleotides at -3 and -2 positions on the efficacy of UUG start codon recognition by the eIF5 G31R mutant, we made 15 different possible HIS4-LacZ reporter constructs.…”

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confidence: 69%

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Sequence-context dependency shown by eIF5^G31Rmutant for UUG start codon selection inSaccharomyces cerevisiae

Ram

2023

Preprint

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In higher eukaryotes, the efficiency of start codon selection depends upon its sequence context A/GxxAUGG, especially at the -3 and +4 position. However, S. cerevisiae prefers AAA/UAUGU sequence context surrounding the AUG start codon. Furthermore, it was demonstrated that the first AUG codon on the mRNA serves as a signal for ribosomal recognition of the initiation site selection. In yeast, the G31R mutation in eIF5 shows Suppressor of initiation codon (Sui) phenotype enabling 40S ribosome to initiate at UUG start codon. To understand whether the UUG codon recognition by the eIF5G31R mutant is sensitive to the sequence context, we made different HIS4-LacZ reporter constructs with UUG as start codon and changed the sequence context at -3 and -2 positions. The HIS4UUG-LacZ transcripts that carry purine (A/G) at the -3-position showed better β-Galactosidase activity than pyrimidine (U/C). Furthermore, on changing the -1 position for the AAA context, we discovered purines are more preferred at the -1 position for the UUG start codon selection.

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Section: Resultsmentioning

confidence: 79%

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confidence: 69%

Sequence-context dependency shown by eIF5^G31Rmutant for UUG start codon selection inSaccharomyces cerevisiae

Ram

2023

Preprint

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“…The toxic and genotoxic consequences of nanomaterials are thought to be modulated by antioxidant enzymes 2 , 34 . In contrast, compared with the Ag-NP-untreated control group, total protein content, and antioxidant enzymes, including CAT, GPx, GST, and SOD levels were substantially lessened in the ovary homogenates of the Ag-NPs treated group 3.…”

Section: Discussionmentioning

confidence: 99%

Insights into Ag-NPs-mediated pathophysiology and ultrastructural aberrations in ovarian tissues of darkling beetles

El-Samad

Hassan

Bakr

et al. 2022

Sci Rep

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With the evolution of nanostructure materials, silver nanoparticles (Ag-NPs) emerged as the predominantly exploited nanomaterial in multifarious sectors due to their versatile properties. Along with the heightening applications of Ag-NPs, however, there is increasing concern over their indubitable toxicity towards the ecosystem, which indeed affects surrounding organisms and human health. In this study, we evaluated the detrimental effects of Ag-NPs in relation to Egyptian wild female beetles, Blaps polychresta, after injection with a single dose of Ag-NPs at different doses and monitoring for 30 days to determine the sublethal dose. Accordingly, the sublethal dose revealed the lowest negative influence was found at 0.03 mg/g body weight. The adverse impacts of Ag-NPs on the ovaries of female beetles were investigated by estimating the enzyme activities, DNA damage using a comet assay, and apoptosis by means of flow cytometry. Besides, the ultrastructural abnormalities were surveyed adopting transmission electron microscopy (TEM). The results manifested comet cells of 7.67 ± 0.88% and 22.33 ± 0.51 for Ag-NPs treated and control groups, respectively. Similarly, the data from flow cytometry demonstrated a substantial reduction in viable cells associated with a significant rise in apoptotic cells for the Ag-NPs treated group in comparison with the control group. Moreover, significant disturbances in enzyme activities for the treated group were perceived correlated with evident diminutions in antioxidant enzymes. Remarkably, the ultrastructural investigation emphasized these findings, exposing considerable deformities of the ovaries in the Ag-NPs treated group compared with the control group. To the best of our knowledge, this is the first report discussing the influence of Ag-NPs at the lowest dose on ovaries of B. polychresta. Collectively, our findings would significantly contribute to considering the critical effects of Ag-NPs at low levels, in addition to the potential use of B. polychresta as a good bio-indicator in ecotoxicological analyses.

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“…It is important to emphasize that the Sui¯ phenotype is caused by the delivery of Met-tRNA i Met in an altered conformation (P IN ) and the attendant premature dissociation of the eIF1 from the scanning 48S ribosomal complex rather than the premature dissociation of Met-tRNA i Met [ 15 , 17 , 18 ]. The defect in the fidelity of start codon selection can have a pleiotropic effect on the cellular proteome and adversely affect cellular physiology [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

eIF2β zinc-binding domain interacts with the eIF2γ subunit through the guanine nucleotide binding interface to promote Met-tRNAiMet binding

Gayen,

Alone

2024

Bioscience Reports

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The heterotrimeric eIF2 complex consists of a core eIF2γ subunit to which binds eIF2α and eIF2β subunits and plays an important role in delivering the Met-tRNAiMet to the 40S ribosome and start codon selection. The intricacies of eIF2β-γ interaction in promoting Met-tRNAiMet binding are not clearly understood. Previously, the zinc-binding domain (ZBD) eIF2βS264Y mutation was reported to cause Met-tRNAiMet binding defect due to the intrinsic GTPase activity. We showed that the eIF2βS264Y mutation has eIF2β-γ interaction defect. Consistently, the eIF2βT238A intragenic suppressor mutation restored the eIF2β-γ and Met-tRNAiMet binding. The eIF2β-ZBD residues Asn252Asp and Arg253Ala mutation caused Met-tRNAiMet binding defect that was partially rescued by the eIF2βT238A mutation, suggesting the eIF2β-ZBD modulates Met-tRNAiMet binding. The suppressor mutation rescued the translation initiation fidelity defect of the eIF2γN135D SW-I mutation and eIF2βF217A/Q221A double mutation in the HTH domain. The eIF2βT238A suppressor mutation could not rescue the eIF2β binding defect of the eIF2γV281K mutation; however, combining the eIF2βS264Y mutation with the eIF2γV281K mutation was lethal. In addition to the previously known interaction of eIF2β with the eIF2γ subunit via its α1-helix, the eIF2β-ZBD also interacts with the eIF2γ subunit via guanine nucleotide-binding interface; thus, the eIF2β-γ interacts via two distinct binding sites.

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Altered proteome in translation initiation fidelity defective eIF5G31R mutant causes oxidative stress and DNA damage

Cited by 5 publications

References 67 publications

Sequence-context dependency shown by eIF5^G31Rmutant for UUG start codon selection inSaccharomyces cerevisiae

Sequence-context dependency shown by eIF5^G31Rmutant for UUG start codon selection inSaccharomyces cerevisiae

Insights into Ag-NPs-mediated pathophysiology and ultrastructural aberrations in ovarian tissues of darkling beetles

eIF2β zinc-binding domain interacts with the eIF2γ subunit through the guanine nucleotide binding interface to promote Met-tRNAiMet binding

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Altered proteome in translation initiation fidelity defective eIF5G31R mutant causes oxidative stress and DNA damage

Cited by 5 publications

References 67 publications

Sequence-context dependency shown by eIF5G31Rmutant for UUG start codon selection inSaccharomyces cerevisiae

Sequence-context dependency shown by eIF5G31Rmutant for UUG start codon selection inSaccharomyces cerevisiae

Insights into Ag-NPs-mediated pathophysiology and ultrastructural aberrations in ovarian tissues of darkling beetles

eIF2β zinc-binding domain interacts with the eIF2γ subunit through the guanine nucleotide binding interface to promote Met-tRNAiMet binding

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Sequence-context dependency shown by eIF5^G31Rmutant for UUG start codon selection inSaccharomyces cerevisiae

Sequence-context dependency shown by eIF5^G31Rmutant for UUG start codon selection inSaccharomyces cerevisiae