Wobble tRNA modification and hydrophilic amino acid patterns dictate protein fate

Rapino, Francesca; Zhou, Zhaoli; Sanchez, Ana Maria Roncero; Joiret, Marc; Seca, Christian; Hachem, Najla El; Valenti, Gianluca; Latini, Sara; Shostak, Kateryna; Geris, Liesbet; Li, Ping; Huang, Gang; Mazzucchelli, Gabriel; Baiwir, Dominique; Desmet, Christophe; Chariot, Alain; Georges, Michel; Close, Pierre

doi:10.1038/s41467-021-22254-5

Cited by 30 publications

(14 citation statements)

References 56 publications

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“…The internal modification of transfer RNA (tRNA) affects the stability of its structure and function and has a significant correlation with protein expression ( Zheng et al, 2017 ). Maladjusted tRNA modification affects the occurrence and development of tumors ( Rapino et al, 2021 ). M7G is a conserved modified nucleoside, which is most often located at the 46th position in the variable region of tRNA.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of 7-methylguanosine and immune microenvironment characteristics in clear cell renal cell carcinomas

Yang²,

Yang³

et al. 2022

Front. Genet.

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Clear cell renal cell carcinoma (ccRCC) is one of the most common tumors in the urinary system. ccRCC has obvious immunological characteristics, and the infiltration of immune cells is related to the prognosis of ccRCC. The effect of immune checkpoint therapy is related to the dynamic changes of the tumor immune microenvironment (TIM). The 7-methylguanosine (m7G) is an additional mRNA modification ability besides m6A, which is closely related to the TIM and affects the occurrence and development of tumors. At present, the correlations between m7G and the immune microenvironment, treatment, and prognosis of ccRCC are not clear. As far as we know, there was no study on the relationship between m7G and the immune microenvironment and survival of clear cell renal cell carcinomas. A comprehensive analysis of the correlations between them and the construction of a prognosis model are helpful to improve the treatment strategy. Two different molecular subtypes were identified in 539 ccRCC samples by describing the differences of 29 m7G-related genes. It was found that the clinical features, TIM, and prognosis of ccRCC patients were correlated with the m7G-related genes. We found that there were significant differences in the expression of PD-1, CTLA4, and PD-L1 between high- and low-risk groups. To sum up, m7G-related genes play a potential role in the TIM, treatment, and prognosis of ccRCC. Our results provide new findings for ccRCC and help to improve the immunotherapy strategies and prognosis of patients.

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Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of 7-methylguanosine and immune microenvironment characteristics in clear cell renal cell carcinomas

Yang²,

Yang³

et al. 2022

Front. Genet.

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“…This finding is supported by prior work in yeast showing that deletion of ribosomal proteins increases readthrough of poly-K and no-go decay (NGD) reporters (13). Knockouts of elongator complex ( ELP3 , ELP4 , ELP5 ) and thiourydilase CTU1, which are required to efficiently decode AAA repeats by modifying U34 of lysyl-tRNA(UUU) (54), decreased the readthrough of poly-K. In addition, deletion of lysyl-tRNA synthetase ( KARS ) which catalyzes the formation of Lys-tRNA Lys selectively increased stalling on poly-K, but not on 102×PR staller, which lacks Lys codons.…”

Section: Resultsmentioning

confidence: 99%

Arginine-rich C9ORF72 ALS Proteins Stall Ribosomes in a Manner Distinct From a Canonical Ribosome-Associated Quality Control Substrate

Kriachkov

McWilliam

Mintern

et al. 2022

Preprint

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Hexanucleotide expansion mutations in C9ORF72 are a cause of familial amyotrophic lateral sclerosis. We previously reported that long arginine-rich dipeptide repeats (DPR), mimicking abnormal proteins expressed from the hexanucleotide expansion, caused translation stalling when expressed in cell culture models. Whether this stalling provides a mechanism of pathogenicity remains to be determined. Here we explored the molecular features of DPR-induced stalling and examined whether known regulatory mechanisms of ribosome quality control (RQC) are involved to sense and resolve the stalls. We demonstrate that arginine-containing DPRs lead to stalling in a length dependent manner, with lengths longer than 40 repeats invoking severe translation arrest. Mutational screening of 40xGly-Xxx DPRs shows that stalling is most pronounced where Xxx are positively charged amino acids (Arg or Lys). Through a genome-wide knockout screen we find that genes regulating stalling on polyadenosine mRNA coding for poly-Lys, a canonical RQC substrate, respond differently to the readthrough of arginine-rich DPRs. Indeed, we find evidence that DPR-mediated stalling has no natural regulatory responses even though the stalls may be sensed, as evidenced by an upregulation of RQC gene expression. These findings therefore implicate arginine-rich DPR-mediated stalled ribosomes as posing a particular danger to cellular health and viability.

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“…Observed changes in the expression of proteins in response to RS might be primarily caused by (a) direct trans-activation of target genes of Nrf2, (b) chronic impact of RS, (c) RS-mediated posttranslational changes and (d) positive- or negative- feedback of protein synthesis rate on transcription of the respective gene(s). We hypothesize that changes in translational efficiency are caused, in part, by aggregation of proteins that might trigger a feedback inhibition of translation, or due to modified amino acids, which alter ribosomal attachment and decoding of mRNA resulting in synthesis of partial or overabundant transcript levels during translation ( 32 – 35 ). Moreover, modified peptides in the CaNrf2-TG may change the redox status through formation of mixed disulfide bonds, which then lead to irreversible protein aggregation in the myocardium ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Tandem Mass Tagging Based Identification of Proteome Signatures for Reductive Stress Cardiomyopathy

Sunny

Jyothidasan

Parsawar

et al. 2022

Front. Cardiovasc. Med.

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Nuclear factor erythroid 2-related factor 2 (NRF2), a redox sensor, is vital for cellular redox homeostasis. We reported that transgenic mice expressing constitutively active Nrf2 (CaNrf2-TG) exhibit reductive stress (RS). In this study, we identified novel protein signature for RS-induced cardiomyopathy using Tandem Mass Tag (TMT) proteomic analysis in heart tissues of TG (CaNrf2-TG) mice at 6–7 months of age. A total of 1,105 proteins were extracted from 22,544 spectra. About 560 proteins were differentially expressed in TG vs. NTg hearts, indicating a global impact of RS on the myocardial proteome. Over 32 proteins were significantly altered in response to RS -20 were upregulated and 12 were downregulated in the hearts of TG vs. NTg mice, suggesting that these proteins could be putative signatures of RS. Scaffold analysis revealed a clear distinction between TG vs. NTg hearts. The majority of the differentially expressed proteins (DEPs) that were significantly altered in RS mice were found to be involved in stress related pathways such as antioxidants, NADPH, protein quality control, etc. Interestingly, proteins that were involved in mitochondrial respiration, lipophagy and cardiac rhythm were dramatically decreased in TG hearts. Of note, we identified the glutathione family of proteins as the significantly changed subset of the proteome in TG heart. Surprisingly, our comparative analysis of NGS based transcriptome and TMT-proteome indicated that ~50% of the altered proteins in TG myocardium was found to be negatively correlated with their transcript levels. In association with the altered proteome the TG mice displayed pathological cardiac remodeling.

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Wobble tRNA modification and hydrophilic amino acid patterns dictate protein fate

Cited by 30 publications

References 56 publications

Comprehensive analysis of 7-methylguanosine and immune microenvironment characteristics in clear cell renal cell carcinomas

Comprehensive analysis of 7-methylguanosine and immune microenvironment characteristics in clear cell renal cell carcinomas

Arginine-rich C9ORF72 ALS Proteins Stall Ribosomes in a Manner Distinct From a Canonical Ribosome-Associated Quality Control Substrate

Tandem Mass Tagging Based Identification of Proteome Signatures for Reductive Stress Cardiomyopathy

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