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Peer-reviewedCC BYProceedings of the National Academy of Sciences of the United States of America

Pyrrolysine supply and demand shapes the translational landscape in Methanosarcina acetivorans.

  • Grace D Britt1
  • Daniel R Utter2
  • Yeonsoo Park3
  • Victoria J Orphan2,3
  • Rodney Tollerson1
  1. 1Department of Biological Sciences, Auburn University, Auburn, AL 36849.
  2. 2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
  3. 3Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, CA 91125.
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Abstract

The amber stop codon (UAG) can encode for pyrrolysine (Pyl) or be read as a stop codon by methylamine-metabolizing organisms including methanogenic archaea. The fate of UAG is decided during the decoding step of translation by competition between the pyrrolysine-aminoacylated transfer RNA (Pyl-tRNAPyl) and release factor. To further understand the consequences of pyrrolysine based genetic code expansion, we integrated RNA sequencing, tRNA charging analysis, and codon-resolved mono- and disome ribosome profiling in Methanosarcina acetivorans. During conditions of high pyrrolysine demand, we observed increased expression of the pyrrolysine biosynthetic operon with a concurrent increase in acylation of tRNAPyl and ribosome occupancy at UAG codons. During low pyrrolysine demand, the population of Pyl-tRNAPyl decreases and we observe a strong ribosome pausing signal during UAG decoding. We find that the dwell time on UAG codons is shorter during high demand, but ribosome collisions increase due to greater ribosome density on UAG-containing transcripts. Together, these results show how pyrrolysine demand modulates tRNA charging and controls elongation dynamics, clarifying the cellular consequences of decoding an ambiguous stop codon.

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Cite

BibTeXRIS
BibTeX
@article{britt2026pyrrolysine,
  title = {{Pyrrolysine supply and demand shapes the translational landscape in Methanosarcina acetivorans.}},
  author = {Grace D Britt and Daniel R Utter and Yeonsoo Park and Victoria J Orphan and Rodney Tollerson},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = oct,
  doi = {10.1073/pnas.2614934123},
  url = {https://europepmc.org/article/MED/42848426},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Pyrrolysine supply and demand shapes the translational landscape in Methanosarcina acetivorans.
AU  - Grace D Britt
AU  - Daniel R Utter
AU  - Yeonsoo Park
AU  - Victoria J Orphan
AU  - Rodney Tollerson
PY  - 2026
DA  - 2026/10/08
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2614934123
UR  - https://europepmc.org/article/MED/42848426
AB  - The amber stop codon (UAG) can encode for pyrrolysine (Pyl) or be read as a stop codon by methylamine-metabolizing organisms including methanogenic archaea. The fate of UAG is decided during the decoding step of translation by competition between the pyrrolysine-aminoacylated transfer RNA (Pyl-tRNAPyl) and release factor. To further understand the consequences of pyrrolysine based genetic code expansion, we integrated RNA sequencing, tRNA charging analysis, and codon-resolved mono- and disome ribosome profiling in Methanosarcina acetivorans. During conditions of high pyrrolysine demand, we observed increased expression of the pyrrolysine biosynthetic operon with a concurrent increase in acylation of tRNAPyl and ribosome occupancy at UAG codons. During low pyrrolysine demand, the population of Pyl-tRNAPyl decreases and we observe a strong ribosome pausing signal during UAG decoding. We find that the dwell time on UAG codons is shorter during high demand, but ribosome collisions increase due to greater ribosome density on UAG-containing transcripts. Together, these results show how pyrrolysine demand modulates tRNA charging and controls elongation dynamics, clarifying the cellular consequences of decoding an ambiguous stop codon.
SN  - 0027-8424
SN  - 1091-6490
ER  -