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J. Biol. Chem., Vol. 281, Issue 46, 35336-35346, November 17, 2006

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Temperature-sensitive eIF5A Mutant Accumulates Transcripts Targeted to the Nonsense-mediated Decay Pathway^*

Rainer Schrader¹, Craig Young, Detlef Kozian, Reinhard Hoffmann^¶, and Friedrich Lottspeich

From the Department for Protein Analytics, Max Planck Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany, Aventis Pharma Germany (GmbH), Brueningstrasse 50, 65929 Frankfurt, Germany, and ^¶Department of Bacteriology, Max von Pettenkofer Institute, Pettenkoferstrasse 9a, 80336 Munich, Germany

The highly conserved protein eIF5A found in Archaea and all eukaryotes uniquely contains the posttranslationally formed amino acid hypusine. Despite being essential the functions of this protein and its modification remain unclear. To gain more insight into these functions temperature-sensitive mutants of the human EIF5A1 were characterized in the yeast Saccharomyces cerevisiae. Expression of the point mutated form V81G in a eIF5A strain of yeast led to a strongly temperature-sensitive phenotype and to a significantly reduced protein level at restrictive temperature. The mutant showed accumulation of a subset of mRNAs that was also observed in nonsense-mediated decay (NMD)-deficient yeast strains. After short incubation at restrictive temperature the mutant exhibited increased half-lives of the intron containing CYH2 pre-mRNA and mature transcripts of NMD-dependent genes. Reduced telomere silencing and shortening was detected in the V81G mutant further supporting similarities to NMD-deficient strains. Our data suggest that eIF5A mediates important cellular processes like cell viability and senescence through its effects on the stability of certain mRNAs.

Received for publication, February 14, 2006 , and in revised form, July 12, 2006.

Primary array datasets were published in the gene expression and hybridization array data repository of the National Center for Biotechnology Information (GEO, http://www.ncbi.nlm.nih.gov/geo/, accession number GSE5290 [NCBI GEO] ).

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Table S1.

¹ To whom correspondence should be addressed: Dept. of Protein Analytics, Max Planck Institute for Biochemistry, Am Klopferspitz 18, 82152 Planegg/Martinsried, Germany. Tel.: 49-89-85-66-21-77; Fax: 49-89-85-78-28-02; E-mail: schrader{at}biochem.mpg.de.

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