ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging

Snieckute, Goda; Ryder, Laura; Vind, Anna Constance; Wu, Zhenzhen; Arendrup, Frederic Schrøder; Stoneley, Mark; Chamois, Sébastien; Martinez-Val, Ana; Leleu, Marion; Dreos, René; Russell, Alexander; Gay, David Michael; Genzor, Aitana Victoria; Choi, Beatrice So-Yun; Basse, Astrid Linde; Sass, Frederike; Dall, Morten; Dollet, Lucile Chantal Marie; Blasius, Melanie; Willis, Anne E.; Lund, Anders H.; Treebak, Jonas T.; Olsen, Jesper Velgaard; Poulsen, Steen Seier; Pownall, Mary Elizabeth; Jensen, Benjamin Anderschou Holbech; Clemmensen, Christoffer; Gerhart-Hines, Zach; Gatfield, David; Bekker-Jensen, Simon

doi:10.1126/science.adf3208

Cited by 41 publications

(15 citation statements)

References 88 publications

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“…In addition to physiological regulation, elongation rates can also be altered by damage to ribosomes or mRNAs. For example, oxidation or UV induced damage to mRNAs can cause ribosomes to stall (Snieckute et al, 2023; Yan et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Dissecting translation elongation dynamics through ultra-long tracking of single ribosomes

Madern,

Yang,

Witteveen

et al. 2024

Preprint

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mRNA translation by ribosomes is a highly dynamic and heterogeneous process. However, current approaches cannot readily resolve individual ribosomes during translation, limiting our understanding of translation dynamics. Here, we develop an imaging approach based on Stopless-ORF circular RNAs (socRNAs) to monitor individual translating ribosomes for hours. Using the socRNA imaging technology we obtained accurate measurements of ribosome pausing on various problematic RNA sequences or induced by ribosome-targeting drugs. In addition, we identified a novel translation factor involved in translation elongation, and revealed that translocation rates of ribosomes vary, indicative of intracellular ribosomal heterogeneity. Finally, socRNAs allow very sensitive measurements of translation elongation fidelity, revealing widespread frameshifting during translation. In summary, our single-ribosome imaging approach provides a detailed view of ribosome translocation kinetics and a powerful new tool to study the translation elongation phase.

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Section: Introductionmentioning

confidence: 99%

Dissecting translation elongation dynamics through ultra-long tracking of single ribosomes

Madern,

Yang,

Witteveen

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…For example, incorrect pre-mRNA processing can produce mRNAs that are prematurely poly-adenylated, resulting in poly(A) sequences within the coding sequence of an mRNA that potently pause ribosomes (Chandrasekaran et al, 2019). Finally, environmental stresses, such as chemical or UV damage, can chemically modify RNA nucleotides in ways that block translation by ribosomes, resulting in ribosome pausing at sites of mRNA damage (Snieckute et al, 2023; Stoneley et al, 2022; Yan et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Ribosome cooperativity promotes fast and efficient translation

Madern,

Yang,

Tanenbaum

2024

Preprint

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The genetic information stored in mRNA is decoded by ribosomes during mRNA translation. mRNAs are typically translated by multiple ribosomes simultaneously, but it is unclear if different ribosomes translating the same mRNA functionally interact with each other. Here, we combine single-ribosome imaging and simulations to compare translation dynamics of individual ribosomes in either monosomes or polysomes to determine how ribosomes interact during translation. We find that ribosomes frequently undergo transient collisions, but that transient collisions, unlike persistent collisions, escape detection by cellular quality control pathways. Instead, our results indicate that transient ribosome collisions promote productive translation by suppressing ribosome pausing when ribosomes encounter problems, a process we term ribosome cooperativity. Ribosome cooperativity also suppresses ribosome recycling on problematic sequences, likely by reducing pause duration, thus stimulating processive translation. Together, our results show that ribosomes cooperate during translation to ensure fast and efficient translation.

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“…Through this process, RQC protects the integrity of mRNA translation and contributes to the maintenance of cellular homeostasis 31,32 . Conversely, defects in RQC, for instance due to depletion of Ltn1 or NEMF, lead to major pathological consequences such as neurological disorders resulting from accumulation of toxic protein aggregates 15,24,33,34 . Nevertheless, while the causal implication of the general mRNA translation machinery in tumorigenesis and therapy resistance is well-documented 12,35 , little is known about the role of RQC in cellular responses to anti-cancer treatments that impact RNA metabolism.…”

Section: Introductionmentioning

confidence: 99%

Ribosome Quality Control Mechanism Mitigates the Cytotoxic Impacts of Ribosome Collisions Induced by 5-Fluorouracil

Chatterjee,

Naeli,

Simms

et al. 2023

Preprint

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Translation of aberrant or damaged mRNAs results in ribosome stalling and collisions. The Ribosome Quality Control (RQC) mechanism detects collided ribosomes and removes aberrant mRNAs and nascent peptides, thus preventing their cytotoxic effects. Conversely, excessive or unresolved ribosome collisions can induce apoptosis. 5-Fluorouracil (5FU) forms the backbone of standard-of-care chemotherapeutic regimens for several types of cancer. Although best known for its incorporation into DNA and inhibition of thymidylate synthase, a major determinant of 5FU’s anticancer activity is its incorporation into RNAs. Nevertheless, the mechanism(s) underlying RNA-dependent 5FU cytotoxicity and the cellular response to its impact on RNA metabolism remain unclear. Here, we report a key role for RQC in mitigating the cytotoxic effects of 5FU-induced dysregulation of mRNA translation. We show that acute 5FU treatment results in the rapid induction of the mTOR signalling pathway, an enhanced rate of mRNA translation initiation, and increased ribosome collisions that trigger RQC. We also found that RQC deficiency, caused by the depletion of ZNF598, results in increased 5FU-induced cell death, a phenotype that is reversed by inhibition of mTOR or repression of mRNA translation initiation. Importantly, 5FU treatment enhances the expression of key RQC factors, including ZNF598 and GIGYF2, via an mTOR-dependent post-translational regulation mechanism. This acute adaptation likely mitigates the cytotoxic consequences of increased ribosome collisions upon 5FU treatment. Overall, our data indicate a heretofore unknown mTOR-dependent mechanism that augments the RQC process, mitigating the cytotoxicity of 5FU and undermining its anticancer efficacy.

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ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging

Cited by 41 publications

References 88 publications

Dissecting translation elongation dynamics through ultra-long tracking of single ribosomes

Dissecting translation elongation dynamics through ultra-long tracking of single ribosomes

Ribosome cooperativity promotes fast and efficient translation

Ribosome Quality Control Mechanism Mitigates the Cytotoxic Impacts of Ribosome Collisions Induced by 5-Fluorouracil

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