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Molecular and Cellular Biology, December 2000, p. 8944-8957, Vol. 20, No. 23
Institute of Genetic
Medicine1 and Howard Hughes Medical
Institute,2 Johns Hopkins University School
of Medicine, Baltimore, Maryland 21205
Received 18 May 2000/Returned for modification 11 July
2000/Accepted 5 September 2000
Transcripts harboring premature signals for translation termination
are recognized and rapidly degraded by eukaryotic cells through a
pathway known as nonsense-mediated mRNA decay (NMD). In addition
to protecting cells by preventing the translation of
potentially deleterious truncated peptides, studies have suggested that
NMD plays a broader role in the regulation of the steady-state levels
of physiologic transcripts. In Saccharomyces
cerevisiae, three trans-acting factors (Upf1p to
Upf3p) are required for NMD. Orthologues of Upf1p have been
identified in numerous species, showing that the NMD machinery, at
least in part, is conserved through evolution. In this study, we
demonstrate additional functional conservation of the NMD pathway
through the identification of Upf2p homologues in
Schizosaccharomyces pombe and humans (rent2). Disruption of
S. pombe UPF2 established that this gene is required for
NMD in fission yeast. rent2 was demonstrated to interact
directly with rent1, a known trans-effector of NMD in
mammalian cells. Additionally, fragments of rent2 were shown to possess
nuclear targeting activity, although the native protein localizes to
the cytoplasmic compartment. Finally, novel functional domains of Upf2p
and rent2 with homology to eukaryotic initiation factor 4G (eIF4G) and
other translational regulatory proteins were identified. Directed
mutations within these so-called eIF4G homology (4GH) domains were
sufficient to abolish the function of S. pombe Upf2p. Furthermore, using the two-hybrid system, we obtained evidence for
direct interaction between rent2 and human eIF4AI and Sui1, both
components of the translation initiation complex. Based on these
findings, a novel model in which Upf2p and rent2 effects decreased
translation and accelerated decay of nonsense transcripts through
competitive interactions with eIF4G-binding partners is proposed.
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Novel Upf2p Orthologues Suggest a Functional Link
between Translation Initiation and Nonsense Surveillance Complexes
*
Corresponding author. Mailing address: Johns Hopkins
University School of Medicine, Ross Building, Room 858, 720 Rutland
Ave., Baltimore, MD 21205. Phone: (410) 614-0701. Fax: (410) 614-2256. E-mail: hdietz{at}jhmi.edu.
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