Attenuation of nonsense-mediated mRNA decay facilitates the response to chemotherapeutics

• Published in: Nature communications Vol. 6; no. 1; p. 6632
• Main Authors: Popp, Maximilian W., Maquat, Lynne E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.03.2015; Nature Publishing Group
• Subjects: 13; 13/1; 13/106; 13/109; 38; 38/77; 631/337/1645/2020; 631/67/1059/99; 631/80/82/23; 631/80/86; 82; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Codon, Nonsense; Cycloheximide - pharmacology; Doxorubicin - pharmacology; Etoposide - pharmacology; HEK293 Cells; HeLa Cells; Humanities and Social Sciences; Humans; Jurkat Cells; MCF-7 Cells; multidisciplinary; Nonsense Mediated mRNA Decay - drug effects; Protein Synthesis Inhibitors - pharmacology; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Trans-Activators - drug effects; Trans-Activators - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7632

Nonsense-mediated mRNA decay (NMD) limits the production of aberrant mRNAs containing a premature termination codon and also controls the levels of endogenous transcripts. Here we show that when human cells are treated with clinically used chemotherapeutic compounds, NMD activity declines partly as a result of the proteolytic production of a dominant-interfering form of the key NMD factor UPF1. Production of cleaved UPF1 functions to upregulate genes involved in the response to apoptotic stresses. The biological consequence is the promotion of cell death. Combined exposure of cells to a small-molecule inhibitor of NMD, NMDI-1, and the chemotherapeutic doxorubicin leads to enhanced cell death, while inhibiting UPF1 cleavage protects cells from doxorubicin challenge. We propose a model to explain why the expression levels of genes producing mRNAs of diverse structure that encode proteins of diverse function are under the purview of NMD. Nonsense-mediated mRNA decay (NMD) is a pathway that controls endogenous transcript levels and limits the production of aberrant mRNAs. Here the authors show that NMD is attenuated in cells treated with chemotherapeutic compounds through caspase-mediated proteolytic cleavage of UPF1, a key NMD effector.