Codon Usage and mRNA Stability are Translational Determinants of Cellular Response to Canonical Ferroptosis Inducers

Rashad, Sherif; Byrne, Shane R.; Saigusa, Daisuke; Xiang, Jingdong; Yuan, Zihao; Zhang, Liyin; Begley, Thomas J.; Tominaga, Teiji; Niizuma, Kuniyasu

doi:10.1016/j.neuroscience.2022.08.009

Cited by 6 publications

(18 citation statements)

References 89 publications

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“…Isoacceptors frequency and total codon frequency were analyzed as we previously reported(Rashad et al, 2022; Tumu et al, 2012). The amino acid normalized codon frequency is calculated as: where isoacceptors refers to the synonymous codons for the amino acid encoded by codon i and n refers to the number of isoacceptors for a given amino acid (2 ≤ n ≤ 6).…”

Section: Methodsmentioning

confidence: 99%

“…tRNA modifications are known to drive mRNA translation by altering codon recognition, usage, and optimality (Chan et al, 2012;Cirzi et al, 2023;Suzuki, 2021). To elucidate the potential for such regulatory fine-tuning on tissue specific mRNA translation, we analyzed three metrics for codon analysis; isoacceptors codon frequency (which measures the ratio of expression between codons belonging to the same amino acids, i.e., isoacceptors), total codon frequency (which measures the ratio of expression between each codon and all other codons, i.e., mRNA codon composition) (Rashad et al, 2022;Tumu et al, 2012), and A-site pausing (which measures the ribosome stalling at each codon) (Liu et al, 2020) 12a]. In addition, the liver, lung, kidney, spleen, and muscle showed strong underusage of the G/C ending codons given the enrichment of such codons in the downregulated genes and relative underusage in the upregulated genes.…”

Section: ⮚ Unique Translational Patterns Observed In Various Tissuesmentioning

confidence: 99%

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tRNA modifications inform tissue specific mRNA translation and codon optimization

Ando,

Rashad,

Begley

et al. 2023

Preprint

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The tRNA epitranscriptome has been recognized as an important player in mRNA translation regulation. tRNA modifications, tRNA expression, and tRNA derived small RNAs (tsRNAs) all play important roles in physiology as well as in multiple pathologies. While the decoding capacity of tRNA is generally understood, there remains gaps in our knowledge of the role of various tRNA processes in fine-tuning translation at the codon level. Specifically, how tRNAs regulates codon usage and bias at the tissue or cell levels remain unexplored. Here, we analyzed seven tissues from mice for the expression of tRNA modifications, mature tRNAs, and tsRNAs. We combined our analysis with Ribo-seq and evaluated various metrics for codon usage and optimality between tissues. Our analysis revealed distinct enrichment patterns of tRNA modifications in tissues. For example, queuosine and mcm5U modifications were most enriched in the brain. In addition, we observed lower levels of tRNAs and tsRNAs in the spleen with higher levels of snRNAs and snoRNAs compared to other tissues. Using three different metrics for codon analysis; isoacceptors frequencies, total codon frequencies, and A-site pausing, we revealed a strong A/T vs G/C ending codons bias in most tissues. The brain was the least biased tissue and was unique compared to all other tissues on multiple levels. Finally, we observed a strong concordance between the expression of queuosine modifications and the optimality of their decoded codons. Our results reveal that tRNA modifications are master regulators of translation and codon usage and optimality across tissues.

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Section: Methodsmentioning

confidence: 99%

Section: ⮚ Unique Translational Patterns Observed In Various Tissuesmentioning

confidence: 99%

tRNA modifications inform tissue specific mRNA translation and codon optimization

Ando,

Rashad,

Begley

et al. 2023

Preprint

Self Cite

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“…group to Undiff. group to get the differentially stabilized genes (DSG) 69 : It was hypothesized that if the stability of mRNAs under the condition of undifferentiation and differentiation changed at the different scale, this will reflect on the fold change values. Genes with Log 2 FC ≥ 1 and adj.…”

Section: Methodsmentioning

confidence: 99%

Dynamic mRNA stability changes buffer transcriptional activation during neuronal differentiation and are regulated by RNA binding proteins

Zhou,

Rashad,

Tominaga

et al. 2023

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The steady state levels of mRNA are outcomes of a finely tuned interplay between RNA transcription and decay. Therefore, the modulation of RNA stability is generally assumed to influence RNA abundance in a positive direction. However, the correlation between mRNA transcription, translation and stability remains elusive. Here, we employed a newly developed simplified mRNA stability profiling technique to explore the role of mRNA stability in SH-SY5Y neuronal differentiation model. Transcriptome-wide mRNA stability analysis revealed neural-specific RNA stability kinetics, including stabilization of transcripts encoding regulators of neuronal morphogenesis and function and destabilization of mitochondrial electron transport and redox homeostasis. When we further examined the relationship between transcription, translation and mRNA stability, a bidirectional regulation of RNA stability was revealed, wherein mRNA stability could either exert the buffering effect on gene products or change in a same direction as transcription. Motif analysis unveiled SAMD4A as a major regulator of the dynamic changes in mRNA stability observed during differentiation. Knockdown of SAMD4A impaired neuronal differentiation and influenced the response to oxidative stress. Mechanistically, SAMD4A was found to alter the stability of several mRNAs to which it binds. Meanwhile, a dimorphic pattern of the correlation between gene expression and SAMD4A-regulated mRNA stability was observed, suggesting dynamic regulation mRNA stability during the neuronal differentiation guided by SAMD4A. The novel insights into the interplay between mRNA stability and cellular behaviors provide a foundation for understanding neurodevelopmental processes and neurodegenerative disorders and highlights dynamic mRNA stability as an important layer of gene expression regulation.

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“…Translational efficiency was calculated by normalizing the Ribo-seq reads to the RNA-seq reads followed by differential expression analysis with Limma-voom using Riborex (https://github.com/smithlabcode/riborex). Codon analysis was conducted as previously reported 44,45,77 .…”

Section: Ribo-seq Data Analysismentioning

confidence: 99%

Angiogenin regulates mitochondrial stress and function via tRNA-derived fragments generation and impacting tRNA modifications

Al-Mesitef,

Tominaga,

Mousa

et al. 2024

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Mitochondrial stress and dysfunction play an important role in many diseases, such as cancer, diabetes, and neurodegenerative diseases. We previously observed that mitochondrial electron transport chain (ETC) inhibition can induce tRNA cleavage and tsRNAs (tRNA-derived small non-coding RNAs) generation. However, whether this process is mediated via Angiogenin (ANG), the canonical enzyme responsible for tRNA cleavage, and whether it has a role in regulating the mitochondrial stress response remains to be understood. ANG is linked to Amyotrophic Lateral Sclerosis (ALS) and other conditions where mitochondrial stress plays a role in pathophysiology. Here, we aimed to examine the role of ANG in regulating the translational response to mitochondrial stress. We observed that ANG protected the cells from respiratory complex III and V inhibition specifically. Furthermore, we validated that the tsRNAs generated during mitochondrial and oxidative stress are mediated by ANG, given that their production is abrogated after ANG knock-out (KO). In addition, we observed that ANG-KO altered the tRNA modification status. Namely, we observed that ANG-KO led to the downregulation of queuosine tRNA modifications (tRNA-Q). tRNA-Q itself is related to mitochondrial translation and function. Indeed, we observed that ANG-KO led to reduced mitochondrial respiration and function. ANG altered how the cells respond to mitochondrial stress by altering the dynamic tRNA modification changes occurring during the stress response. We further examined the impact of ANG-KO on stress granules (SG) assembly as well as the knockdown of G3BP1 (core protein of SGs) on tsRNAs generation. Our results indicate that ANG regulates mitochondrial function and stress via tsRNAs generation as well as altering tRNA modifications levels. Our data also indicate that there are no direct links between tRNA cleavage and SG assembly, and both could be parallel systems for translation repression during stress.

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Codon Usage and mRNA Stability are Translational Determinants of Cellular Response to Canonical Ferroptosis Inducers

Cited by 6 publications

References 89 publications

tRNA modifications inform tissue specific mRNA translation and codon optimization

tRNA modifications inform tissue specific mRNA translation and codon optimization

Dynamic mRNA stability changes buffer transcriptional activation during neuronal differentiation and are regulated by RNA binding proteins

Angiogenin regulates mitochondrial stress and function via tRNA-derived fragments generation and impacting tRNA modifications

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