Seryl-tRNA synthetase promotes translational readthrough by mRNA binding and involvement of the selenocysteine incorporation machinery.
Abstract
Translational readthrough of UGA stop codons by selenocysteine-specific tRNA (tRNASec) enables the synthesis of selenoproteins. Seryl-tRNA synthetase (SerRS) charges tRNASec with serine, which is modified into selenocysteine and delivered to the ribosome by a designated elongation factor (eEFSec in eukaryotes). Here we found that components of the human selenocysteine incorporation machinery (SerRS, tRNASec, and eEFSec) also increased translational readthrough of non-selenocysteine genes, including VEGFA, to create C-terminally extended isoforms. SerRS recognizes target mRNAs through a stem-loop structure that resembles the variable loop of its cognate tRNAs. This function of SerRS depends on both its enzymatic activity and a vertebrate-specific domain. Through eCLIP-seq, we identified additional SerRS-interacting mRNAs as potential readthrough genes. Moreover, SerRS overexpression was sufficient to reverse premature termination caused by a pathogenic nonsense mutation. Our findings expand the repertoire of selenoprotein biosynthesis machinery and suggest an avenue for therapeutic targeting of nonsense mutations using endogenous factors.
Publication Types
Keywords
MeSH Terms
Funding
Linked Datasets (1)
Seryl-tRNA synthetase promotes translational readthrough via mRNA binding by involving the selenocysteine incorporation machinery
Homo sapiens12 data files
| File | Type | Size |
|---|---|---|
| SLA_101.fastq.gz | OTHER | 1.7 GB |
| SLA_101.fastq.gz | OTHER | 1.7 GB |
| SLA_102.fastq.gz | OTHER | 1.5 GB |
| SLA_102.fastq.gz | OTHER | 1.5 GB |
| SLA_89.fastq.gz | OTHER | 1.5 GB |
| SLA_89.fastq.gz | OTHER | 1.5 GB |
| SLA_95.fastq.gz | OTHER | 1.9 GB |
| SLA_95.fastq.gz | OTHER | 1.9 GB |
| SLA_97.fastq.gz | OTHER | 1.7 GB |
| SLA_97.fastq.gz | OTHER | 1.7 GB |
| SLA_99.fastq.gz | OTHER | 1.8 GB |
| SLA_99.fastq.gz | OTHER | 1.8 GB |
Potentially Related Datasets (2)
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.