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Nonsense-mediated RNA decay: an emerging modulator of malignancy

Abstract

Nonsense-mediated RNA decay (NMD) is a highly conserved RNA turnover pathway that selectively degrades RNAs harbouring truncating mutations that prematurely terminate translation, including nonsense, frameshift and some splice-site mutations. Recent studies show that NMD shapes the mutational landscape of tumours by selecting for mutations that tend to downregulate the expression of tumour suppressor genes but not oncogenes. This suggests that NMD can benefit tumours, a notion further supported by the finding that mRNAs encoding immunogenic neoantigen peptides are typically targeted for decay by NMD. Together, this raises the possibility that NMD-inhibitory therapy could be of therapeutic benefit against many tumour types, including those with a high load of neoantigen-generating mutations. Complicating this scenario is the evidence that NMD can also be detrimental for many tumour types, and consequently tumours often have perturbed NMD. NMD may suppress tumour generation and progression by degrading subsets of specific normal mRNAs, including those encoding stress-response proteins, signalling factors and other proteins beneficial for tumours, as well as pro-tumour non-coding RNAs. Together, these findings suggest that NMD-modulatory therapy has the potential to provide widespread therapeutic benefit against diverse tumour types. However, whether NMD should be stimulated or repressed requires careful analysis of the tumour to be treated.

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Fig. 1: The nonsense-mediated RNA decay pathway.
Fig. 2: Signals that trigger nonsense-mediated RNA decay and contexts that permit nonsense-mediated RNA decay escape.
Fig. 3: The dual role of nonsense-mediated RNA decay in cancer.
Fig. 4: Nonsense-mediated RNA decay degrades mRNAs encoding neoantigens.
Fig. 5: Putative mechanisms by which nonsense-mediated RNA decay suppresses malignancy.
Fig. 6: Nonsense-mediated RNA decay modulatory therapy.

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Acknowledgements

This study was funded by NIH R01 HD093846 (M.F.W.), as well as NIH R01 CA247562 and NIH R01 CA244182 (D.G.S.).

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All authors researched data for the article, substantially contributed to discussion of content and wrote, reviewed, and edited the manuscript before submission.

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Correspondence to Dwayne G. Stupack or Miles F. Wilkinson.

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Glossary

RNA turnover

Degradation of RNAs; typically achieved through the action of specific nucleases.

Premature termination codons

(PTCs). Stop codons created by a mutation that prematurely terminates translation. PTC-bearing genes encode truncated proteins.

Nonsense mutations

Substitutions of a single base pair that leads to the appearance of a stop codon where previously there was a codon specifying an amino acid.

Frameshift mutations

Insertions and deletions downstream of the initiator codon that are not a multiple of 3, thereby shifting the reading frame. This results in a sequence of amino acids different from that in the original protein. Typically, a premature termination codon is also generated, which results in decay of the mRNA by nonsense-mediated RNA decay.

Neoantigen

Non-self amino acid residue generated as a result of somatic mutations, including frameshift mutations. Such sequences are recognized as foreign when they are generated after the immune tolerance phase of fetal development.

Untranslated region

(UTR). The region of an mRNA upstream and downstream of the coding region. The 5′ UTR is upstream of the initiator codon and the 3′ UTR is downstream of the stop codon.

Passenger mutations

Mutations that have no discernible effect on cell fitness but are associated with clonal expansion simply because they occur in the same genome that harbours driver mutations.

Missense mutations

Genetic alterations in which a single base pair substitution alters the genetic code in a way that produces an amino acid that is different from the usual amino acid at that position.

Synonymous mutations

Changes in the DNA sequence that alter the codon but do not change the encoded amino acid (due to redundancy of the genetic code).

PTC readthrough-inducing compounds

Small molecules that enable the ribosomal machinery to read a stop codon as a codon encoding an amino acid, often resulting in the expression of a full-length functional protein.

Exon-junction complex

A protein complex deposited near most exon–exon junctions following RNA splicing. It stimulates nonsense-mediated RNA decay and also regulates several other post-transcriptional events.

Dominant-negative proteins

Mutant proteins that antagonize the function of the wild type protein.

Microsatellite instability

(MSI). Deficient DNA mismatch repair in tumours, which as a consequence makes them prone to hypermutation.

Immune checkpoint inhibitors

(ICIs). Drugs that block checkpoint proteins (negative regulatory proteins) in immune cells. ICI therapy derepresses immune function and thereby enhances adaptive immune responses (that is, T cell and B cell responses).

Epithelial-to-mesenchymal transition

(EMT). A critical developmental process co-opted by tumours in which epithelial cells acquire mesenchymal traits, including their migratory and invasive properties.

Staufen-mediated mRNA decay

An mRNA decay pathway in competition with nonsense-mediated RNA decay that depends on the RNA-binding protein Staufen 1 or Staufen 2 and the RNA helicase up-frameshift 1 (UPF1).

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Tan, K., Stupack, D.G. & Wilkinson, M.F. Nonsense-mediated RNA decay: an emerging modulator of malignancy. Nat Rev Cancer 22, 437–451 (2022). https://doi.org/10.1038/s41568-022-00481-2

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