Nucleic Acids Research, 1995, Vol. 23, No. 19 3980-3988
© 1995
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Sequences 5' of the first upstream open reading frame in GCN4 mRNA are required for efficient translational reinitiation
Section on Molecular Genetics of Lower Eukaryotes, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development Bethesda, MD 20892, USA
*To whom corresponde should be addressed
Received May 11, 1995. Revised August 6, 1995. Accepted August 6, 1995.
Translation of yeast GCN4 mRNA occurs by a reinitiation mechanism that is modulated by amino acid levels in the cell. Ribosomes which translate the first of four upstream open reading frames (uORFs) in the mRNA leader resume scanning and can reinitiate downstream. Under non-starvation conditions reinitiation occurs at one of the remaining three uORFs and GCN4 is repressed. Under starvation conditions, in contrast, ribosomes bypass the uORFs and reinitiate at GCN4 instead. The high frequency of reinitiatlon following uORF1 translation depends on an adequate distance to the next start codon and particular sequences surrounding the uORF1 stop codon. We present evidence that sequences 5' to uORF1 aiso strongly enhance reinitiation. First, reinitlation was severely inhibited when uORF1 was transplanted into the position of uORF4, even though the native sequence environment of the uORF1 stop codon was main tained, and this effect could not be accounted for by the decreased uORF1-GCN4 spacing. Second, insertions and deletions in the leader preceding uORF1 greatly reduced reinitiatlon at GCN4. Sequences 5' to uORF1 may influence the probability of ribosome release following peptide termination at uORF1. Alter natively, they may facilitate rebinding of an initiation factor required for reinitiatlon prior to resumption of the scanning process.
*Present addresses: School of Biochemistry and Molecular Genetics. University of New South Wales, Sydney 2052, Australia and Infection Diseases Department, Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, MI 48106-1047, USA
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