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  4. Codon-specific ribosome stalling reshapes translational dynamics during branched-chain amino acid starvation
 
research article

Codon-specific ribosome stalling reshapes translational dynamics during branched-chain amino acid starvation

Worpenberg, Lina  
•
Gobet, Cédric  
•
Naef, Félix  
September 27, 2025
Genome Biology

Background Cells regulate protein synthesis in response to fluctuating nutrient availability through mechanisms that affect both translation initiation and elongation. Branched-chain amino acids, leucine, isoleucine, and valine, are essential nutrients. However, how their depletion affects translation remains largely unclear. Here, we investigate the immediate effects of single, double, and triple branched-chain amino acid deprivation on translational dynamics in NIH3T3 cells using RNA-seq and ribosome profiling. Results All starvation conditions increased ribosome dwell times, with pronounced stalling at all valine codons during valine and triple starvation, whereas leucine and isoleucine starvation produced milder, codon-specific effects. Notably, stalling under isoleucine deprivation largely decreased under triple starvation. Positional enrichment of valine codons near the 5′ end and downstream isoleucine codons potentially contributes to these patterns, suggesting a possible elongation bottleneck that influences translational responses under branched-chain amino acid starvation. The presence of multiple valine stalling sites was associated with decreased protein levels. Finally, codon-specific dwell time changes correlated strongly with patterns of tRNA isoacceptor charging. Conclusions Together, these findings suggest that differential ribosome stalling under branched-chain amino acid starvation reflects a balance between amino acid supply, tRNA charging dynamics, codon position, and stress-response signaling.

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Type
research article
DOI
10.1186/s13059-025-03800-6
Author(s)
Worpenberg, Lina  

École Polytechnique Fédérale de Lausanne

Gobet, Cédric  

École Polytechnique Fédérale de Lausanne

Naef, Félix  

École Polytechnique Fédérale de Lausanne

Date Issued

2025-09-27

Publisher

Springer Science and Business Media LLC

Published in
Genome Biology
Volume

26

Issue

1

Article Number

315

Subjects

Translation regulation

•

Ribosome profiling

•

Amino acid starvation

•

tRNA charging

•

Codon-specific stalling

•

Elongation bottleneck

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Nutrient stress response

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
UPNAE  
FunderFunding(s)Grant NumberGrant URL

Swiss National Science Foundation

205884

Available on Infoscience
October 3, 2025
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/254600
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