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Updated: Jul 19, 2025
Xenopus laevis as a Model to Identify Translation Impairment
Published on: September 27, 2015
Decoding of translation-regulating entities reveals heterogeneous translation deficiency patterns in cellular
Angelos Papaspyropoulos1,2, Orsalia Hazapis1, Abdullah Altulea3
1Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.
Abstract:
Cellular senescence constitutes a generally irreversible proliferation barrier, accompanied by macromolecular damage and metabolic rewiring. Several senescence types have been identified based on the initiating stimulus, such as replicative (RS), stress-induced (SIS) and oncogene-induced senescence (OIS). These senescence subtypes are heterogeneous and often develop subset-specific phenotypes. Reduced protein synthesis is considered a senescence hallmark, but whether this trait pertains to various senescence subtypes and if distinct molecular mechanisms are involved remain largely unknown. Here, we analyze large published or experimentally produced RNA-seq and Ribo-seq datasets to determine whether major translation-regulating entities such as ribosome stalling, the presence of uORFs/dORFs and IRES elements may differentially contribute to translation deficiency in senescence subsets. We show that translation-regulating mechanisms may not be directly relevant to RS, however uORFs are significantly enriched in SIS. Interestingly, ribosome stalling, uORF/dORF patterns and IRES elements comprise predominant mechanisms upon OIS, strongly correlating with Notch pathway activation. Our study provides for the first time evidence that major translation dysregulation mechanisms/patterns occur during cellular senescence, but at different rates depending on the stimulus type. The degree at which those mechanisms accumulate directly correlates with translation deficiency levels. Our thorough analysis contributes to elucidating crucial and so far unknown differences in the translation machinery between senescence subsets.
Insights
Cellular senescence involves distinct translation regulation differences. Oncogene-induced senescence (OIS) primarily uses ribosome stalling, uORF/dORF patterns, and IRES elements, unlike other senescence types.
Area of Science:
- Molecular Biology
- Cell Biology
- Genomics
Background:
- Cellular senescence is a state of irreversible cell cycle arrest with metabolic changes.
- Different senescence types (replicative, stress-induced, oncogene-induced) exhibit unique phenotypes.
- Reduced protein synthesis is a hallmark of senescence, but its underlying mechanisms across subtypes are unclear.
Purpose of the Study:
- To investigate differential contributions of translation regulation mechanisms to protein synthesis deficiency in various senescence subtypes.
- To explore the roles of ribosome stalling, upstream open reading frames (uORFs)/downstream open reading frames (dORFs), and internal ribosome entry site (IRES) elements in senescence.
Main Methods:
- Analysis of large RNA-seq and Ribo-seq datasets from published and experimental sources.
- Comparative analysis of translation regulation patterns across replicative senescence (RS), stress-induced senescence (SIS), and oncogene-induced senescence (OIS).
Main Results:
- Translation-regulating mechanisms are not directly linked to RS.
- uORFs are significantly enriched in SIS.
- Ribosome stalling, uORF/dORF patterns, and IRES elements are predominant in OIS, correlating with Notch pathway activation.
- The extent of these mechanisms directly correlates with translation deficiency levels.
Conclusions:
- Major translation dysregulation mechanisms in cellular senescence vary significantly depending on the initiating stimulus.
- Specific patterns of ribosome stalling, uORFs/dORFs, and IRES elements characterize OIS, linked to Notch signaling.
- This study reveals critical, previously unknown differences in the translation machinery across senescence subsets.
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