Nonsense-mediated RNA decay: an emerging modulator of malignancy

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.

Automated summary

Nonsense-mediated RNA decay (NMD) is a highly conserved RNA turnover pathway that selectively degrades RNAs harboring truncating mutations, which can affect the expression of tumor suppressor genes and oncogenes. NMD may have a dual role in tumors, as it can promote tumor growth by downregulating the expression of tumor suppressor genes and degrade immunogenic neoantigen peptides, but it can also suppress tumor generation and progression by degrading specific normal mRNAs and non-coding RNAs beneficial for tumors. NMD-modulatory therapy has the potential to provide widespread therapeutic benefit against diverse tumor types, but careful analysis is needed to determine whether NMD should be stimulated or repressed in specific tumors.