Translation initiation downstream from annotated start codons in human mRNAs coevolves with the Kozak context
Autor: | Dmitri B. Papkovsky, Pavel V. Baranov, Maria S. Benitez-Cantos, Martina M. Yordanova, Dmitry E. Andreev, Patrick B F O'Connor, Alexander V. Zhdanov, Sergey I. Kovalchuk |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Codon
Initiator Leaky scanning Context (language use) Computational biology Biology Ribosome Evolution Molecular 03 medical and health sciences 0302 clinical medicine Eukaryotic translation Start codon Genetics Humans Ribosome profiling RNA Messenger Peptide Chain Initiation Translational Gene Genetics (clinical) Conserved Sequence 030304 developmental biology 0303 health sciences Base Sequence Research Proteins Translation (biology) Protein synthesis Ribosomes 030217 neurology & neurosurgery |
Zdroj: | Genome Res Digibug: Repositorio Institucional de la Universidad de Granada Universidad de Granada (UGR) Digibug. Repositorio Institucional de la Universidad de Granada instname |
Popis: | Eukaryotic translation initiation involves preinitiation ribosomal complex 5′ -to-3′ directional probing of mRNA for codons suitable for starting protein synthesis. The recognition of codons as starts depends on the codon identity and on its immediate nucleotide context known as Kozak context. When the context is weak (i.e., nonoptimal), leaky scanning takes place during which a fraction of ribosomes continues the mRNA probing. We explored the relationship between the context of AUG codons annotated as starts of protein-coding sequences and the next AUG codon occurrence. We found that AUG codons downstream from weak starts occur in the same frame more frequently than downstream from strong starts. We suggest that evolutionary selection on in-frame AUGs downstream from weak start codons is driven by the advantage of the reduction of wasteful out-of-frame product synthesis and also by the advantage of producing multiple proteoforms from certain mRNAs. We confirmed translation initiation downstream from weak start codons using ribosome profiling data. We also tested translation of alternative start codons in 10 specific human genes using reporter constructs. In all tested cases, initiation at downstream start codons was more productive than at the annotated ones. In most cases, optimization of Kozak context did not completely abolish downstream initiation, and in the specific example of CMPK1 mRNA, the optimized start remained unproductive. Collectively, our work reveals previously uncharacterized forces shaping the evolution of protein-coding genes and points to the plurality of translation initiation and the existence of sequence features influencing start codon selection, other than Kozak context. Russian Science Foundation (RSF) 20-14-00121 Science Foundation Ireland 210692/Z/18/Z Science Foundation Ireland 12/RC/2276_P2 Erasmus+ Programme Plan Propio de Investigacion 2019 de la Universidad de Granada Ministry of Economy of Spain DPI2017-84439-R European Union (EU) DPI2017-84439-R |
Databáze: | OpenAIRE |
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