title: Coding region polyadenylation generates a truncated tRNA synthetase that counters translation repression.
abstract: Posttranscriptional regulatory mechanisms superimpose "fine-tuning" control upon "on-off" switches characteristic of gene transcription. We have exploited computational modeling with experimental validation to resolve an anomalous relationship between mRNA expression and protein synthesis. The GAIT (gamma-interferon-activated inhibitor of translation) complex repressed VEGF-A synthesis to a low, constant rate independent of VEGF-A mRNA expression levels. Dynamic model simulations predicted an inhibitory GAIT-element-interacting factor to account for this relationship and led to the identification of a truncated form of glutamyl-prolyl tRNA synthetase (EPRS), a GAIT constituent that mediates binding to target transcripts. The truncated protein, EPRS(N1), shields GAIT-element-bearing transcripts from the inhibitory GAIT complex, thereby dictating a "translational trickle" of GAIT target proteins. EPRS(N1) mRNA is generated by polyadenylation-directed conversion of a Tyr codon in the EPRS-coding sequence to a stop codon (PAY(∗)). Genome-wide analysis revealed multiple candidate PAY(∗) targets, including the authenticated target RRM1, suggesting a general mechanism for production of C terminus-truncated regulatory proteins.
authors.affiliation: Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Yao
authors.forename: Alka A
authors.initials: AA
authors.lastname: Potdar
authors.forename: Abul
authors.initials: A
authors.lastname: Arif
authors.forename: Partho Sarothi
authors.initials: PS
authors.lastname: Ray
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukhopadhyay
authors.forename: Belinda
authors.initials: B
authors.lastname: Willard
authors.forename: Yichi
authors.initials: Y
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Saidel
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
mesh_terms: D000595:Amino Acid Sequence; D000604:Amino Acyl-tRNA Synthetases / Q000737:chemistry / Q000235:genetics*; D018388:Codon, Terminator; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D026723:Polyadenylation; D014176:Protein Biosynthesis; D059467:Transcriptome; D020298:U937 Cells; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D018388:Codon, Terminator; D046912:Multiprotein Complexes; D042461:Vascular Endothelial Growth Factor A; D000604:Amino Acyl-tRNA Synthetases; C415462:glutamyl-prolyl-tRNA synthetase