To NMD or not to NMD: nonsense-mediated mRNA decay in cancer and other genetic diseases

Abstract

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.

This work was funded by the European Research Council (ERC) starting grant HYPER-INSIGHT ( 757700 , to F.S.) and ERC consolidator grant IR-DC ( 616434 to B.L.). F.S. and B.L. are funded by the ICREA Research Professor program. F.S. and B.L. acknowledge support of the Severo Ochoa Centres of Excellence program to the IRB Barcelona and to the CRG, respectively. B.L. and F.S. were supported by the Fondo Europeo de Desarrollo Regional (FEDER)/ Ministerio de Ciencia, Innovación y Universidades - Agencia Estatal de Investigación projects BFU2017-89488-P and RegioMut ( BFU2017-89833-P ), respectively. B.L. was further supported by the Bettencourt Schueller Foundation , the Agencia de Gestio d'Ajuts Universitaris i de Recerca ( 2017 SGR 1322 ), and the Centres de Recerca de Catalunya (CERCA) program/ Generalitat de Catalunya . B.L. also acknowledges the support of the Spanish Ministry of Economy, Industry, and Competitiveness to the European Molecular Biology Laboratory (EMBL) partnership