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Coding Region Polyadenylation Generates a Truncated tRNA Synthetase that Counters Translation Repression

2012; Cell Press; Volume: 149; Issue: 1 Linguagem: Inglês

10.1016/j.cell.2012.02.018

1097-4172

Peng Yao, Alka A. Potdar, Abul Arif, Partho Sarothi Ray, Rupak Mukhopadhyay, Belinda Willard, Yichi Xu, Jun Yan, Gerald M. Saidel, Paul L. Fox,

RNA Research and Splicing

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, EPRSN1, shields GAIT-element-bearing transcripts from the inhibitory GAIT complex, thereby dictating a “translational trickle” of GAIT target proteins. EPRSN1 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.