Chaperone-directed ribosome repair after oxidative damage

Yang, Yoon-Mo; Jung, Young-Eun; Abegg, Daniel; Adibekian, Alexander; Carroll, Kate S.; Karbstein, Katrin

doi:10.1016/j.molcel.2023.03.030

Cited by 27 publications

(16 citation statements)

References 72 publications

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“…RPS26 inclusion into pre-40S together with other factors facilitates final step of 40S subunit maturation (Plassart et al , 2021). Moreover, Tsr2 mediates the disassembly of Rps26 from mature 40S subunit in cytoplasm in high salt and pH conditions (Yang & Karbstein, 2022) or when Rps26 is oxidized (Yang et al , 2023).…”

Section: Resultsmentioning

confidence: 99%

“…This could be explained by the fact that insufficiency of TSR2 may affect incorporation of RPS26 during nuclear maturation (Schütz et al , 2018) or cytoplasmic regeneration of 40S (Yang et al , 2023), thus having an effect on FMRpolyG biosynthesis. Overall, this data strengthens our conclusion regarding the positive effect of RPS26 and TSR2 on RAN translation initiated from the near-cognate ACG or GUG codons located in the 5’UTR of FMR1 .…”

Section: Resultsmentioning

confidence: 99%

“…The silencing of this chaperon also exhibited selectivity towards FMRpolyG over the FMRP reading frame without affecting the other 40S ribosomal proteins, such as RACK1, RPS6, and RPS15 (Figure 4A&B). Previously, it was shown that Tsr2 is responsible for replacing damaged Rps26, which undergoes oxidation on mature 80S ribosomes under stress conditions (Yang et al , 2023). Therefore, the activity of this chaperon may play an important role in modulating RAN translation via Rps26 assembly or disassembly from ribosomal subunits, also during different stresses (Yang & Karbstein, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Silencing TSR2 did not affect the level of other components of the 40S subunits such as RACK1, RPS6 and RPS15, however, the level of a known responder of RPS26 insufficiency, Histone H3.3 (Li et al, 2022), was significantly reduced (Figure 4A&B). This could be explained by the fact that insufficiency of TSR2 may affect incorporation of RPS26 during nuclear maturation (Schütz et al, 2018) or cytoplasmic regeneration of 40S (Yang et al, 2023), thus having an effect on FMRpolyG biosynthesis. Overall, this data strengthens our conclusion regarding the positive effect of RPS26 and TSR2 on RAN translation initiated from the near-cognate ACG or GUG codons located in the 5'UTR of FMR1.…”

Section: Tsr2 Mediates the Ran Translation Of Fmrpolyg Perhaps Via Rps26mentioning

confidence: 99%

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Insufficiency of 40S ribosomal proteins, RPS26 and RPS25, negatively affects biosynthesis of polyglycine-containing proteins in fragile-X associated conditions

Tutak,

Broniarek,

Zielezinski

et al. 2024

Preprint

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Expansion of CGG repeats (CGGexp) in the 5′ untranslated region (5′UTR) of the FMR1 gene underlies the fragile X-associated conditions including tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disease. One pathomechanism of FXTAS is the repeat-associated non-AUG-initiated (RAN) translation of CGG repeats of mutant FMR1 mRNA, resulting in production of FMRpolyG, a toxic protein containing long polyglycine tract. To identify novel modifiers of RAN translation we used an RNA-tagging system and mass spectrometry-based screening. It revealed proteins enriched on CGGexp-containing FMR1 RNA in cellulo, including a ribosomal protein RPS26, a component of the 40S subunit. We demonstrated that RPS26, together with its chaperone TSR2, modulates FMRpolyG production and its toxicity. We also found that the number of proteins produced via RPS26-sensitive translation was limited, and 5′UTRs of mRNAs encoding these proteins were guanosine and cytosine-rich. Moreover, the silencing of another component of the 40S subunit, the ribosomal protein RPS25, also induced repression of FMRpolyG biosynthesis. Results of this study suggest that the composition of the 40S subunit plays important role in noncanonical CGGexp-related RAN translation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Tsr2 Mediates the Ran Translation Of Fmrpolyg Perhaps Via Rps26mentioning

confidence: 99%

See 2 more Smart Citations

Insufficiency of 40S ribosomal proteins, RPS26 and RPS25, negatively affects biosynthesis of polyglycine-containing proteins in fragile-X associated conditions

Tutak,

Broniarek,

Zielezinski

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Furthermore, the cell has also developed systems to recognise and replace damaged cellular components 16 . This is the case for oxidised cytosolic ribosomal proteins which are released from ribosomes through a chaperon-mediated ribosome repair mechanism 17 . Given the high levels of ROS in the mitochondria and the key role played by mitochondrial translation for cancer cell fitness 4,18,19 , it is unclear how oxidative damage is prevented at mitochondrial ribosomes.…”

Section: Introductionmentioning

confidence: 99%

ROSALINDprotects the mitochondrial translational machinery from oxidative damage

Katopodi,

Verheyden,

Cinque

et al. 2024

Preprint

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Upregulation of mitochondrial respiration coupled with high ROS-scavenging capacity is a characteristic shared by drug-tolerant cells in several cancers. As translational fidelity is essential for cell fitness, protection of the mitochondrial and cytosolic ribosomes from oxidative damage is pivotal. While mechanisms for recognizing and repairing such damage exist in the cytoplasm, the corresponding process in the mitochondria remains unclear.By performing Ascorbate PEroXidase (APEX)-proximity ligation assay directed to the mitochondrial matrix followed by isolation and sequencing of RNA associated to mitochondrial proteins, we identified the nuclear-encoded lncRNAROSALINDas an interacting partner of ribosomes.ROSALINDis upregulated in recurrent tumours and its expression can discriminate between responders and non-responders to immune checkpoint blockade in a melanoma cohort of patients. Featuring an unusually high G content,ROSALINDserves as a substrate for oxidation. Consequently, inhibitingROSALINDleads to an increase in ROS and protein oxidation, resulting in severe mitochondrial respiration defects. This, in turn, impairs melanoma cell viability and increases immunogenicity bothin vitroandex vivoin preclinical humanized cancer models. These findings underscore the role ofROSALINDas a novel ROS buffering system, safeguarding mitochondrial translation from oxidative stress, and shed light on potential therapeutic strategies for overcoming cancer therapy resistance.

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ACDMBI: A deep learning model based on community division and multi-source biological information fusion predicts essential proteins

Lu,

Tian

2024

Computational Biology and Chemistry

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Chaperone-directed ribosome repair after oxidative damage

Cited by 27 publications

References 72 publications

Insufficiency of 40S ribosomal proteins, RPS26 and RPS25, negatively affects biosynthesis of polyglycine-containing proteins in fragile-X associated conditions

Insufficiency of 40S ribosomal proteins, RPS26 and RPS25, negatively affects biosynthesis of polyglycine-containing proteins in fragile-X associated conditions

ROSALINDprotects the mitochondrial translational machinery from oxidative damage

ACDMBI: A deep learning model based on community division and multi-source biological information fusion predicts essential proteins

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