Named after Selene, goddess of the moon selenocysteine (Sec) is unique in its unrivaled catalytic power and its insertion into proteins by redefinition of specific UGA stop codons to Sec. In their Communication on page 319 ff., D. Söll, P. O'Donoghue et al. describe the engineering of the Sec-insertion machinery to redefine nearly all 64 codons. Here, the ring-shaped decameric selenocysteine synthase SeIA is essential in providing tRNA-bound Sec as the central building block for selenoprotein translation.

The trace element selenium is found in proteins as selenocysteine (Sec), the 21st amino acid to participate in ribosome-mediated translation. The substrate for ribosomal protein synthesis is selenocysteinyl-tRNA ^Sec . Its biosynthesis from seryl-tRNA ^Sec has been established for bacteria, but the mechanism of conversion from Ser-tRNA ^Sec remained unresolved for archaea and eukarya. Here, we provide evidence for a different route present in these domains of life that requires the tRNA ^Sec -dependent conversion of O -phosphoserine (Sep) to Sec. In this two-step pathway, O -phosphoseryl-tRNA ^Sec kinase (PSTK) converts Ser-tRNA ^Sec to Sep-tRNA ^Sec . This misacylated tRNA is the obligatory precursor for a Sep-tRNA:Sec-tRNA synthase (SepSecS); this protein was previously annotated as SLA/LP. The human and archaeal SepSecS genes complement in vivo an Escherichia coli Sec synthase (SelA) deletion strain. Furthermore, purified recombinant SepSecS converts Sep-tRNA ^Sec into Sec-tRNA ^Sec in vitro in the presence of sodium selenite and purified recombinant E. coli selenophosphate synthetase (SelD). Phylogenetic arguments suggest that Sec decoding was present in the last universal common ancestor. SepSecS and PSTK coevolved with the archaeal and eukaryotic lineages, but the history of PSTK is marked by several horizontal gene transfer events, including transfer to non-Sec-decoding Cyanobacteria and fungi.

Das nach Selene, der Mondgöttin benannte Selenocystein (Sec) zeichnet sich durch eine einzigartige Katalysekraft und die Insertion in Proteine durch die Umkodierung spezifischer UGA-Stopcodons zu Sec aus. In der Zuschrift auf S. 325 ff. beschreiben D. Söll, P. O'Donoghue et al. die Entwicklung einer Sec-Insertions-Maschinerie, um fast alle 64 Codons umzukodieren. Dabei ist die ringförmige decamere Selenocystein-Synthase SeIA für die Bereitstellung von tRNA-gebundenem Sec als zentralem Baustein für die Selenoproteintranslation essenziell.

Significance: Pyrrolysyl-tRNA synthetase (PylRS) and its cognate tRNA ^Pyl have emerged as ideal translation components for genetic code innovation. We found that a series of PylRS variants that were initially selected to be specific for the posttranslational modification N ^ε -acetyl- l -Lys displayed polyspecificity [i.e., activity with a broad range of noncanonical amino acid (ncAA) substrates]. Our structural and biochemical data indicate that the engineered tRNA synthetases can accommodate ncAA substrates in multiple binding modes. The data further suggest that in vivo selections do not produce optimally specific tRNA synthetases and that translation fidelity will become an increasingly dominant factor in expanding the genetic code far beyond 20 amino acids.

Perfectly accurate translation of mRNA into protein is not a prerequisite for life. Resulting from errors in protein synthesis, mistranslation occurs in all cells, including human cells. The human genome encodes >600 tRNA genes, providing both the raw material for genetic variation and a buffer to ensure that resulting translation errors occur at tolerable levels. On the basis of data from the 1000 Genomes Project, we highlight the unanticipated prevalence of mistranslating tRNA variants in the human population and review studies on synthetic and natural tRNA mutations that cause mistranslation or de-regulate protein synthesis. Although mitochondrial tRNA variants are well known to drive human diseases, including developmental disorders, few studies have revealed a role for human cytoplasmic tRNA mutants in disease. In the context of the unexpectedly large number of tRNA variants in the human population, the emerging literature suggests that human diseases may be affected by natural tRNA variants that cause mistranslation or de-regulate tRNA expression and nucleotide modification. This review highlights examples relevant to genetic disorders, cancer, and neurodegeneration in which cytoplasmic tRNA variants directly cause or exacerbate disease and disease-linked phenotypes in cells, animal models, and humans. In the near future, tRNAs may be recognized as useful genetic markers to predict the onset or severity of human disease.