To NMD or Not To NMD: Nonsense-Mediated mRNA Decay in Cancer and Other Genetic Diseases

The nonsense-mediated mRNA decay (NMD) pathway degrades some but not all mRNAs bearing premature termination codons (PTCs). Decades of work have elucidated the molecular mechanisms of NMD. More recently, statistical analyses of large genomic datasets have allowed the importance of known and novel 'rules of NMD' to be tested and combined into methods that accurately predict whether PTC-containing mRNAs are degraded or not. We discuss these genomic approaches and how they can be applied to identify diseases and individuals that may benefit from inhibition or activation of NMD. We also discuss the importance of NMD for gene editing and tumor evolution, and how inhibiting NMD may be an effective strategy to increase the efficacy of cancer immunotherapy. Genomic analyses have quantified the importance of known and novel 'rules of nonsense-mediated mRNA decay (NMD)', allowing accurate prediction of whether premature termination codon (PTC)-containing mRNAs are degraded or not.NMD can both aggravate and alleviate the effects of PTCs that cause genetic disease, and this varies across both diseases and individuals.Overall, NMD more frequently aggravates the effects of detrimental, disease-causing mutations.NMD frequently inactivates tumor-suppressor genes and silences the expression of neoantigens in cancer.NMD inhibition may be an effective strategy to enhance cancer immunotherapy and to treat a wide variety of genetic diseases.