Mistranslating tRNA identifies a deleterious S213P mutation in the allele.

Mistranslation occurs when an amino acid not specified by the standard genetic code is incorporated during translation. Since the ribosome does not read the amino acid, tRNA variants aminoacylated with a non-cognate amino acid or containing a non-cognate anticodon dramatically increase the frequency of mistranslation. In a systematic genetic analysis, we identified a suppression interaction between tRNA, which mistranslates proline codons by inserting serine, and , a temperature sensitive allele of the gene encoding an acetyltransferase required for sister chromatid cohesion. The suppression was partial, with a tRNA that inserts alanine at proline codons and not apparent for a tRNA that inserts serine at arginine codons. Sequencing of the allele revealed a mutation that would convert the highly conserved serine 213 within β7 of the GCN5-related -acetyltransferase core to proline. Mutation of P213 in back to the wild-type serine restored the function of the enzyme at elevated temperatures. Our results indicate the utility of mistranslating tRNA variants to identify functionally relevant mutations and identify as a reporter for mistranslation. We propose that mistranslation could be used as a tool to treat genetic disease.