Codon Bias Confers Stability to mRNAs via ILF2 in Humans

Hia, Fabian; Yang, Sheng Fan; Shichino, Yuichi; Yoshinaga, Masanori; Murakawa, Yuji; Vandenbon, Alexis; Fukao, Akira; Fujiwara, Toshinobu; Landthaler, Markus; Natsume, Tohru; Adachi, Shungo; Iwasaki, Shigeo; Takeuchi, Osamu

doi:10.1101/585992

Cited by 6 publications

(8 citation statements)

References 48 publications

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“…Positive PC1 values correlate with genes with low GC3 content (and high AT3), while negative PC1 values correlate with genes with high GC3 content (and low AT3). It has been recently reported that GC3 codons are associated with human mRNA stability and with higher translation efficiency, thereby increasing protein production 19 .…”

Section: Transgene Codon Usage Impacts Oncolytic Adenoviral Replicationmentioning

confidence: 99%

Transgene codon usage drives viral fitness and therapeutic efficacy in oncolytic adenoviruses

Núñez-Manchón

Farrera-Sal

Castellano

et al. 2020

Preprint

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Arming oncolytic adenoviruses with therapeutic transgenes is a well-established strategy for multimodal tumour attack. However, this strategy sometimes leads to unexpected attenuated viral replication and a loss of oncolytic effects, preventing these viruses from reaching the clinic. Previous work has shown that altering codon usage in viral genes can hamper viral fitness. Here, we have analysed how transgene codon usage impacts viral replication and oncolytic activity. We observe that, although transgenes with optimised codons show high expression levels at a first round of infection, they impair viral fitness and are therefore not expressed in a sustained manner. Conversely, transgenes encoded by suboptimal codons do not compromise viral replication and are thus stably expressed over time allowing a greater oncolytic activity both in vitro and in vivo. Altogether, our work shows that fine-tuning codon usage leads to a concerted optimisation of transgene expression and viral replication paving the way for the rational design of more efficacious oncolytic therapies.

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Section: Transgene Codon Usage Impacts Oncolytic Adenoviral Replicationmentioning

confidence: 99%

Transgene codon usage drives viral fitness and therapeutic efficacy in oncolytic adenoviruses

Núñez-Manchón

Farrera-Sal

Castellano

et al. 2020

Preprint

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“…This reflects the biological importance of codon pairs in modulating translational efficiency(84)(85)(86). Codon bias measures (and their changes due to mutation) were also of high importance (starting at second highest rank), in line with the abundant evidence of the relationship between codon composition and a variety of biologically-relevant factors, including gene expression(49,87,88), translational efficiency(14,89,90), and mRNA stability(91)(92)(93)(94). Since codon selection modulates translational speed and thus cotranslational folding(95), sSNVs can also affect protein structure (96) without altering protein sequence.…”

mentioning

confidence: 67%

Decoding the effects of synonymous variants

Zeng

Aptekmann

Bromberg

2021

Preprint

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Synonymous single nucleotide variants (sSNVs) are common in the human genome but are often overlooked. However, sSNVs can have significant biological impact and may lead to disease. Existing computational methods for evaluating the effect of sSNVs suffer from the lack of gold-standard training/evaluation data and exhibit over-reliance on sequence conservation signals. We developed synVep (synonymous Variant effect predictor), a machine learning-based method that overcomes both of these limitations. Our training data was a combination of variants reported by gnomAD (observed) and those unreported, but possible in the human genome (generated). We used positive-unlabeled learning to purify the generated variant set of any likely unobservable variants. We then trained two sequential extreme gradient boosting models to identify subsets of the remaining variants putatively enriched and depleted in effect. Our method attained 90% precision/recall on a previously unseen set of variants. Furthermore, although synVep does not explicitly use conservation, its scores correlated with evolutionary distances between orthologs in cross-species variation analysis. synVep was also able to differentiate pathogenic vs. benign variants, as well as splice-site disrupting variants (SDV) vs. non-SDVs. Thus, synVep provides an important improvement in annotation of sSNVs, allowing users to focus on variants that most likely harbor effects. Availability: synVep webserver for online query: https://services.bromberglab.org/synvep; For local runs Python script (https://bitbucket.org/bromberglab/synvep_local) and prediction database (https://zenodo.org/record/4763256) are also available.

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“…However, the destabilizing effects of codon pairs are only weakly correlated with known effects of GC content, synonymous codon usage, or amino acid content on mRNA stability (Fig. S1A-C) (12)(13)(14)(15). Among the twenty amino acids, the positively charged amino acids lysine and arginine cause the largest average decreases in mRNA levels (Fig.…”

Section: A Massively Parallel Assay For Mrna Levels In Human Cellsmentioning

confidence: 98%

“…Two studies implicated synonymous codon choice as the primary determinant of mRNA stability in human cells (12,13). Another found GC and GC3 (wobble base GC) content as major factors regulating mRNA stability (14). A fourth study identi ed amino acid content to be an important contributor (15).…”

Section: Introductionmentioning

confidence: 99%

A Nascent Peptide Code for Translational Control of mRNA Stability in Human Cells

Burke¹,

Park²,

Subramaniam³

2021

Preprint

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Stability of eukaryotic mRNAs is associated with their codon, amino acid, and GC content. Yet, coding sequence motifs that predictably alter mRNA stability in human cells remain poorly defined. Here, we develop a massively parallel assay to measure mRNA effects of thousands of synthetic and endogenous coding sequence motifs in human cells. We identify several families of simple dipeptide repeats whose translation triggers acute mRNA instability. Rather than individual amino acids, specific combinations of bulky and positively charged amino acids are critical for the destabilizing effects of dipeptide repeats. Remarkably, dipeptide sequences that form extended β strands in silico and in vitro drive ribosome stalling and mRNA instability in vivo. The resulting nascent peptide code underlies ribosome stalling and mRNA-destabilizing effects of hundreds of endogenous peptide sequences in the human proteome. Our work reveals an intrinsic role for the ribosome as a selectivity filter against the synthesis of bulky and aggregation-prone peptides.

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Codon Bias Confers Stability to mRNAs via ILF2 in Humans

Cited by 6 publications

References 48 publications

Transgene codon usage drives viral fitness and therapeutic efficacy in oncolytic adenoviruses

Transgene codon usage drives viral fitness and therapeutic efficacy in oncolytic adenoviruses

Decoding the effects of synonymous variants

A Nascent Peptide Code for Translational Control of mRNA Stability in Human Cells

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