Short tRNA anticodon stem and mutant eRF1 allow stop codon reassignment

Ambar Kachale, Zuzana Pavlíková, Anna Nenarokova, Adriana Roithová, Ignacio M. Durante, Petra Miletínová, Kristína Záhonová, Serafim Nenarokov, Jan Votýpka, Eva Horáková, Robert L. Ross, Vyacheslav Yurchenko, Petra Beznosková, Zdeněk Paris (), Leoš Shivaya Valášek () and Julius Lukeš ()
Additional contact information
Ambar Kachale: Institute of Parasitology, Biology Centre, Czech Academy of Sciences
Zuzana Pavlíková: Institute of Microbiology, Czech Academy of Sciences
Anna Nenarokova: Institute of Parasitology, Biology Centre, Czech Academy of Sciences
Adriana Roithová: Institute of Microbiology, Czech Academy of Sciences
Ignacio M. Durante: Institute of Parasitology, Biology Centre, Czech Academy of Sciences
Petra Miletínová: Institute of Microbiology, Czech Academy of Sciences
Kristína Záhonová: Institute of Parasitology, Biology Centre, Czech Academy of Sciences
Serafim Nenarokov: Institute of Parasitology, Biology Centre, Czech Academy of Sciences
Jan Votýpka: Institute of Parasitology, Biology Centre, Czech Academy of Sciences
Eva Horáková: Institute of Parasitology, Biology Centre, Czech Academy of Sciences
Robert L. Ross: Thermo Fisher Scientific
Vyacheslav Yurchenko: University of Ostrava
Petra Beznosková: Institute of Microbiology, Czech Academy of Sciences
Zdeněk Paris: Institute of Parasitology, Biology Centre, Czech Academy of Sciences
Leoš Shivaya Valášek: Institute of Microbiology, Czech Academy of Sciences
Julius Lukeš: Institute of Parasitology, Biology Centre, Czech Academy of Sciences

Nature, 2023, vol. 613, issue 7945, 751-758

Abstract: Abstract Cognate tRNAs deliver specific amino acids to translating ribosomes according to the standard genetic code, and three codons with no cognate tRNAs serve as stop codons. Some protists have reassigned all stop codons as sense codons, neglecting this fundamental principle1–4. Here we analyse the in-frame stop codons in 7,259 predicted protein-coding genes of a previously undescribed trypanosomatid, Blastocrithidia nonstop. We reveal that in this species in-frame stop codons are underrepresented in genes expressed at high levels and that UAA serves as the only termination codon. Whereas new tRNAsGlu fully cognate to UAG and UAA evolved to reassign these stop codons, the UGA reassignment followed a different path through shortening the anticodon stem of tRNATrpCCA from five to four base pairs (bp). The canonical 5-bp tRNATrp recognizes UGG as dictated by the genetic code, whereas its shortened 4-bp variant incorporates tryptophan also into in-frame UGA. Mimicking this evolutionary twist by engineering both variants from B. nonstop, Trypanosoma brucei and Saccharomyces cerevisiae and expressing them in the last two species, we recorded a significantly higher readthrough for all 4-bp variants. Furthermore, a gene encoding B. nonstop release factor 1 acquired a mutation that specifically restricts UGA recognition, robustly potentiating the UGA reassignment. Virtually the same strategy has been adopted by the ciliate Condylostoma magnum. Hence, we describe a previously unknown, universal mechanism that has been exploited in unrelated eukaryotes with reassigned stop codons.

Date: 2023
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DOI: 10.1038/s41586-022-05584-2

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