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

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  • Maximilian W. Popp

    (School of Medicine and Dentistry, University of Rochester
    Center for RNA Biology, University of Rochester)

  • Lynne E. Maquat

    (School of Medicine and Dentistry, University of Rochester
    Center for RNA Biology, University of Rochester)

Abstract

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.

Suggested Citation

  • Maximilian W. Popp & Lynne E. Maquat, 2015. "Attenuation of nonsense-mediated mRNA decay facilitates the response to chemotherapeutics," Nature Communications, Nature, vol. 6(1), pages 1-17, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7632
    DOI: 10.1038/ncomms7632
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    Cited by:

    1. Hanae Sato & Robert H. Singer, 2021. "Cellular variability of nonsense-mediated mRNA decay," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

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