bims-protra 2025-11-23 papers

Issue of 2025–11–23
three papers selected by
Marius d’Hervé, McGill University

Nat Biotechnol. 2025 Nov 21.

Programmable initiation of mRNA translation by trans-RNA.

Longfei Jia, Tan-Trung Nguyen, Saori Uematsu, Yifei Gu, Shengcho Shi, Yaser Hashem, Shu-Bing Qian.

Several approaches exist to silence genes, but few tools are available to activate individual mRNAs for translation inside cells. Guiding ribosomes to specific start codons without altering the original sequence remains a formidable task. Here we design capped trans-RNAs capable of directing ribosomes to specific initiation sites on individual mRNAs when the trans-cap is positioned near the target start codon. Structural and biochemical data suggest that the capped trans-RNA facilitates ribosome loading and scanning on the target mRNA through a synergistic mechanism involving alternative cap recognition. The trans-RNA also acts independently of the cap on the target mRNA, enabling translation of circular RNAs lacking internal ribosome entry sites. We apply trans-RNAs in vivo to achieve programmable alternative translation of endogenous genes in mouse liver. Finally, we provide the evidence for the existence of natural transcripts that, similarly to exogenous trans-RNAs, activate translation of endogenous mRNAs.

DOI: https://doi.org/10.1038/s41587-025-02897-1

J Biol Chem. 2025 Nov 19. pii: S0021-9258(25)02810-8. [Epub ahead of print] 110958

From The Integrated Stress Response to Oxidative Stress; A Historical Perspective.

Mehdi Amiri, Phoenix Toboz, Michael A Bellucci, Soroush Tahmasebi, Nahum Sonenberg.

Oxidative stress has exerted fundamental evolutionary pressure since the emergence of aerobic life. Its impact on the physiology and function of all organisms is profound and consequential for cell survival. The integrated stress response (ISR) plays a critical role in counteracting oxidative stress via translational control of a subset of mRNAs. Here, we summarize the fundamental discoveries that shaped our understanding of the ISR pathway's role in cellular adaptation to oxidative stress from studies of protein synthesis in reticulocyte lysates to the regulation of glutathione metabolism downstream of the ISR pathway. We describe recent advances in studying mRNA translation changes in response to oxidative stress based on high throughput translatome analyses.

Keywords: Glutathione; ISR; Oxidative Stress; eIF2; mRNA Translation

DOI: https://doi.org/10.1016/j.jbc.2025.110958

Biochem Biophys Res Commun. 2025 Nov 16. pii: S0006-291X(25)01687-0. [Epub ahead of print]792 152971

Interplay between codon usage and ribosome heterogeneity: A new layer of translational regulation.

Ujwal Dahal, Anu Bansal, Anshu Raj Dahal, Mukti Ram Aryal, Barsha Khanal.

Codon usage bias (CUB) and ribosome heterogeneity represent two fundamental yet traditionally separate dimensions of translational regulation. CUB, defined as the preferential use of synonymous codons, influences translation efficiency, fidelity, mRNA stability, and protein folding. Ribosome heterogeneity, arising from variability in ribosomal RNA modifications, ribosomal protein composition, and tissue-specific paralogs, generates specialized ribosomes with selective mRNA translation capacity. Emerging evidence reveals that these two regulatory axes are functionally interconnected: specialized ribosomes preferentially translate transcripts enriched in distinct codon usage patterns, regulating protein synthesis during development, stress adaptation, and disease progression. This interplay reshapes the classical view of translation by integrating codon context with ribosome specialization, forming a "ribosome code" that governs proteome composition. Disruption of this axis contributes to diverse diseases, including cancer, ribosomopathies, and neurodevelopmental disorders, where codon-specific translational reprogramming drives pathogenic protein expression. Advances in ribosome profiling, cryo-EM, and integrative computational modeling have illuminated these dynamics at unprecedented resolution, offering new opportunities for targeted therapeutic interventions. This review synthesizes current knowledge on codon-ribosome interactions, explores their mechanistic basis and functional implications, and highlights future research directions toward decoding this emerging layer of translational control.

Keywords: Codon usage bias; RNA modification; Ribosome heterogeneity; Specialized ribosomes; Translational regulation

DOI: https://doi.org/10.1016/j.bbrc.2025.152971