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

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. 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. 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. changes in the number of genomic copies of chromosomal segments, resulting from duplication or deletion of DNA. a protein assembly that usually remains deposited on the mRNA near the splice site after splicing. a decrease/increase in the ability of cells or organisms to survive or to reproduce. a type of cancer treatment that boosts the ability of the immune system to clear cancerous cells. decrease/increase of the frequency of a genotype in a population as a result of fitness loss/gain by cells or individuals carrying that genotype. antigens expressed on tumor cells, but not on normal cells, that can trigger an immune response and that derive from mutated or aberrantly expressed proteins. a passive process in which NMD fails to recognize and degrade a PTC-bearing transcript. a stop codon that occurs 5' to the normal stop codon in the transcript as the result of a mutation or altered splicing. also termed protein truncation, a protein that is shortened because a mutation has interrupted its translation, which can impair its function. the total number of mutations in the tumor genome or exome.