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SerRS mediates translational readthrough of through engagement of the selenocysteine incorporation machinery

ABSTRACT: Translational readthrough of UGA stop codons by selenocysteine-specific tRNAs (tRNASec) provide the basis for selenoprotein biosynthesis. Seryl-tRNA synthetase (SerRS) charges tRNASec with serine, which is modified into selenocysteine, and delivered to the ribosome by a designated elongation factor (eEFSec). We found that the selenocysteine incorporation machinery, including SerRS, tRNASec, and eEFSec, also mediated translational readthrough of non-selenocysteine genes, including VEGFA, to create C-terminally extended protein isoforms. SerRS bound a subset of non-selenocysteine mRNAs to facilitate serine insertion. SerRS-mediated readthrough is sufficient to reverse premature termination caused by a disease-causing nonsense mutation. Genes involved in hypoxia, angiogenesis, and adhesion are enriched among SerRS-bound genes. This regulatory function of SerRS in mRNA translation is dependent on its enzymatic activity but also a vertebrate-specific domain involved in non-tRNA nucleic acid interaction. Our findings offer an avenue for therapeutic targeting of nonsense mutations through regulation of existing protein synthesis machinery exclusively using unmodified factors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206674 | GEO | 2026/06/11

REPOSITORIES: GEO

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Seryl-tRNA synthetase promotes translational readthrough via mRNA binding by involving the selenocysteine incorporation machinery

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