A reassessment of the translation initiation codon in vertebrates.

More than two decades ago Marilyn Kozak proposed the scanning model of translation initiation, whereby translation is initiated at the first AUG codon that is in a particular context. In this article, we re-examine the context of initiator codons using a large dataset of curated human transcripts. We find that more than 40% of transcripts contain AUG codons upstream of the actual start codon and that most authentic AUGs contain three or more mismatches from the consensus sequence, CCACCaugG. Also, in a large fraction of transcripts, the sequences surrounding the initiator codon deviate more from the consensus than those surrounding upstream AUGs, indicating that translation initiation from downstream AUGs is more common than generally believed.

[1]  Timothy B. Stockwell,et al.  The Sequence of the Human Genome , 2001, Science.

[2]  M. Kozak.  An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. , 1987, Nucleic acids research.

[3]  K. Katz,et al.  Introducing RefSeq and LocusLink: curated human genome resources at the NCBI. , 2000, Trends in genetics : TIG.

[4]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[5]  J. Basso,et al.  The chicken c-Jun 5′ untranslated region directs translation by internal initiation , 2000, Oncogene.

[6]  S. Brunak,et al.  Prediction of N-terminal protein sorting signals. , 1997, Current opinion in structural biology.

[7]  N. Gray,et al.  Control of translation initiation in animals. , 1998, Annual review of cell and developmental biology.

[8]  R. Jackson,et al.  Internal initiation of translation in eukaryotes: the picornavirus paradigm and beyond. , 1995, RNA.

[9]  A K Hopper,et al.  mRNA leader length and initiation codon context determine alternative AUG selection for the yeast gene MOD5. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[10]  M. Kozak,et al.  How do eucaryotic ribosomes select initiation regions in messenger RNA? , 1978, Cell.

[11]  Anders Krogh,et al.  Prediction of Signal Peptides and Signal Anchors by a Hidden Markov Model , 1998, ISMB.

[12]  M. Kozak.  Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. , 1984, Nucleic acids research.

[13]  A. Levinson,et al.  Initiation of translation at internal AUG codons in mammalian cells , 1984, Nature.

[14]  M. Spiess,et al.  Heads or tails — what determines the orientation of proteins in the membrane , 1995, FEBS letters.

[15]  B. Blagoev,et al.  Common pitfalls in bioinformatics-based analyses: look before you leap. , 2001, Trends in genetics : TIG.

[16]  K. Nakai.  Protein sorting signals and prediction of subcellular localization. , 2000, Advances in protein chemistry.

[17]  M. Kozak.  Possible role of flanking nucleotides in recognition of the AUG initiator codon by eukaryotic ribosomes. , 1981, Nucleic acids research.

[18]  M. MacFarlane,et al.  Initiation of Apaf-1 translation by internal ribosome entry , 2000, Oncogene.

[19]  A. Prats,et al.  Alternative translation of human fibroblast growth factor 2 mRNA occurs by internal entry of ribosomes , 1995, Molecular and cellular biology.