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Molecular and Cellular Biology, January 2001, p. 209-223, Vol. 21, No. 1
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.1.209-223.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Identification and Characterization of Human Orthologues to Saccharomyces cerevisiae Upf2 Protein and Upf3 Protein (Caenorhabditis elegans SMG-4)

Guillaume Serin,1,2 Anand Gersappe,1 Jennifer D. Black,3 Rachel Aronoff,4 and Lynne E. Maquat1,2,*

Department of Cancer Genetics1 and Department of Experimental Therapeutics,3 Roswell Park Cancer Institute, Buffalo, New York 14263; Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York 146422; and Max-Planck Institute for Medical Research, Molecular Neuroscience, D-69120 Heidelberg, Germany4

Received 19 May 2000/Returned for modification 17 August 2000/Accepted 19 September 2000

Nonsense-mediated mRNA decay (NMD), also called mRNA surveillance, is an important pathway used by all organisms that have been tested to degrade mRNAs that prematurely terminate translation and, as a consequence, eliminate the production of aberrant proteins that could be potentially harmful. In mammalian cells, NMD appears to involve splicing-dependent alterations to mRNA as well as ribosome-associated components of the translational apparatus. To date, human (h) Upf1 protein (p) (hUpf1p), a group 1 RNA helicase named after its Saccharomyces cerevisiae orthologue that functions in both translation termination and NMD, has been the only factor shown to be required for NMD in mammalian cells. Here, we describe human orthologues to S. cerevisiae Upf2p and S. cerevisiae Upf3p (Caenorhabditis elegans SMG-4) based on limited amino acid similarities. The existence of these orthologues provides evidence for a higher degree of evolutionary conservation of NMD than previously appreciated. Interestingly, human orthologues to S. cerevisiae Upf3p (C. elegans SMG-4) derive from two genes, one of which is X-linked and both of which generate multiple isoforms due to alternative pre-mRNA splicing. We demonstrate using immunoprecipitations of epitope-tagged proteins transiently produced in HeLa cells that hUpf2p interacts with hUpf1p, hUpf3p-X, and hUpf3p, and we define the domains required for the interactions. Furthermore, we find by using indirect immunofluorescence that hUpf1p is detected only in the cytoplasm, hUpf2p is detected primarily in the cytoplasm, and hUpf3p-X localizes primarily to nuclei. The finding that hUpf3p-X is a shuttling protein provides additional indication that NMD has both nuclear and cytoplasmic components.

* Corresponding author. Mailing address: Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642. Phone: (716) 273-5640. Fax: (716) 271-2683. E-mail: lynne_maquat{at}urmc.rochester.edu.

Molecular and Cellular Biology, January 2001, p. 209-223, Vol. 21, No. 1
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.1.209-223.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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