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Translation elongation inhibitors stabilize select transcripts

ABSTRACT: The ribosome is central to cellular stress responses because it serves as a sensor to activate signaling pathways that determine cell fate. While the activation of these signaling pathways by translation elongation inhibitors has been well characterized, the impact of these inhibitors on mRNA dynamics remains unclear. Here we use TimeLapse sequencing to investigate how translational stress impacts mRNA dynamics in human cells. Our results reveal that a distinct group of transcripts is stabilized in response to the translation elongation inhibitor emetine. These stabilized mRNAs are short-lived at steady state and many of them encode C2H2 zinc finger proteins. The codon compositions of these stabilized transcripts are suboptimal compared to short-lived mRNAs that are not stabilized. Finally, we show that stabilization of these transcripts is independent of the signaling pathways activated by ribosome collisions, as well as of canonical ribosome quality control factors. Our data describe a group of transcripts whose degradation is particularly sensitive to the inhibition of translation elongation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264661 | GEO | 2024/10/01

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE264661_HD_log2fc_July2023.csv.gz	Csv
	GSE264661_LD_log2fc_July2023.csv.gz	Csv
	GSE264661_cB.csv.gz	Csv
	GSE264661_ercc_spike.csv.gz	Csv

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Ribosome Profiling Reveals Pervasive Translation Outside of Annotated Protein-Coding Genes

Project description:Ribosome profiling suggests that ribosomes occupy many regions of the transcriptome thought to be non-coding, including 5' UTRs and lncRNAs. Apparent ribosome footprints outside of protein-coding regions raise the possibility of artifacts unrelated to translation, particularly when they occupy multiple, overlapping open reading frames (ORFs). Here we show hallmarks of translation in these footprints: co-purification with the large ribosomal subunit, response to drugs targeting elongation, trinucleotide periodicity, and initiation at early AUGs. We develop a metric for distinguishing between 80S footprints and nonribosomal sources using footprint size distributions, which validates the vast majority of footprints outside of coding regions. We present evidence for polypeptide production beyond annotated genes, including induction of immune responses following human cytomegalovirus (HCMV) infection. Translation is pervasive on cytosolic transcripts outside of conserved reading frames, and direct detection of this expanded universe of translated products enables efforts to understand how cells manage and exploit its consequences. Ribosome profiling to verify that true ribosome footprints shift in response to different elongation inhibitors (CHX vs Emetine) and co-purify with an affinity-tagged large ribosomal subunit (bound vs input)

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Unresolved stalled ribosome complexes restrict cycle progression after genotoxic stress

Project description:Translation of damaged mRNA can lead to ribosome stalling, thereby producing incomplete proteins toxic to the cell. The mechanism of ribosome-associated quality control (RQC) disassembles stalled ribosomes through the actions of the ASC-1 complex (ASCC). Here, we show that some reagents that chemically damage RNA, such as ultraviolet light (UV), cause ribosome stalling, which leads to accumulation of the ASC-1 complex (ASCC) on stalled ribosomes and stable interaction of the ASCC3 helicase with RNA. In contrast, the ASCC was not similarly affected by emetine or anisomycin-induced ribosome stalling. Our work identified two different types of stalled ribosome. Ribosomes arrested by emetine or anisomycin are transient as they are resolved by the ASCC. Whereas the ASCC fails to split some stalled ribosomes, such as those induced by UV, resulting in long-lived stalled ribosome complexes. We show that ribosome stalling activates the G1/S and G2/M cell cycle checkpoints with long-lived stalled ribosomes causing prolonged checkpoint activation. Thus, the cell adjusts this adaptive survival response to match the nature of the stalled ribosome.

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Unresolved stalled ribosome complexes restrict cycle progression after genotoxic stress

2022-02-07 | PXD023976 | Pride

Unresolved stalled ribosome complexes restrict cycle progression after genotoxic stress

2022-02-07 | PXD023978 | Pride

Unresolved stalled ribosome complexes restrict cycle progression after genotoxic stress

2022-02-07 | PXD023861 | Pride

Distinct stages of the translation elongation cycle revealed by sequencing ribosome-protected mRNA fragments

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2019-09-10 | PXD014357 | Pride

GTPBP1 resolves paused ribosomes to maintain neuronal homeostasis

Project description:Ribosome-associated quality control pathways respond to defects in translational elongation to recycle arrested ribosomes and degrade aberrant polypeptides and mRNAs. Loss of an individual tRNA gene leads to ribosomal pausing that is resolved by the translational GTPase GTPBP2, and in its absence causes neuron death. Here we show that loss of the homologous protein GTPBP1 during tRNA deficiency in the mouse brain also leads to codon-specific ribosome pausing and neurodegeneration, suggesting that these non-redundant translational GTPases function in the same pathway to mitigate ribosome pausing. Ribosome stalling in the mutant brain led to activation of the integrated stress response (ISR) mediated by GCN2 and decreased mTORC1 signaling. However, in contrast to the ISR, which enhanced neuron survival, reduced mTORC1 signaling increased neuronal death. Our data demonstrate that GTPBP1 functions as an important quality control mechanism during translation elongation and suggest that translational signaling pathways intricately interact to regulate neuronal homeostasis during defective translation elongation.

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