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.
Highlights
Nonsense-mediated mRNA decay (NMD) limits the production of aberrant mRNAs containing a premature termination codon and controls the levels of endogenous transcripts
We propose that the efficiency of NMD can be tuned by extracellular stimuli, and one purpose for the NMD-mediated control of endogenous gene expression is to assist in the establishment of a particular state by tailoring the mRNA milieu to one that can respond to potentially diverse stimuli
We examined the stability of a panel of known NMD target mRNAs34 in human MCF7 breast cancer cells during doxorubicin treatment
Summary
Nonsense-mediated mRNA decay (NMD) limits the production of aberrant mRNAs containing a premature termination codon and controls the levels of endogenous transcripts. During muscle cell differentiation in humans and rodents, NMD efficiency is downregulated, while the efficiency of a competing pathway, Staufen-mediated mRNA decay, is upregulated[8,9]. These changes tailor the mRNA pool to favour the expression of promyogenic factors[8,9]. Concomitant with a decrease in cellular viability is a global decrease in mRNA levels[30,31] Superimposed on these changes are proteolytic events, carried out by caspase enzymes that actively promote apoptosis and dismantle the cell[32,33]. We propose that the efficiency of NMD can be tuned by extracellular stimuli, and one purpose for the NMD-mediated control of endogenous gene expression is to assist in the establishment of a particular state by tailoring the mRNA milieu to one that can respond to potentially diverse stimuli
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