title: Attenuation of nonsense-mediated mRNA decay facilitates the response to chemotherapeutics.
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.
authors: 1] Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, USA [2] Center for RNA Biology, University of Rochester, Rochester, New York 14642, USA.
authors: Maximilian W
authors: MW
authors: Popp
authors: 1] Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, USA [2] Center for RNA Biology, University of Rochester, Rochester, New York 14642, USA.
authors: Lynne E
authors: LE
authors: Maquat
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D018389:Codon, Nonsense; D003513:Cycloheximide / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D061986:MCF-7 Cells; D059365:Nonsense Mediated mRNA Decay / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D020365:RNA Helicases; D012333:RNA, Messenger / Q000378:metabolism*; D015534:Trans-Activators / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018389:Codon, Nonsense; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D015534:Trans-Activators; D005047:Etoposide; D004317:Doxorubicin; D003513:Cycloheximide; D020365:RNA Helicases; C101828:UPF1 protein, human