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Peer-reviewedCC BYNature communications

The PAXT connection is a modifier of rare codon-enriched protein expression.

  • Taylor Niehoff1
  • Jackson Peterson1
  • Siqi Li1
  • Sijin Chen2
  • Christopher V Nicchitta3
  • Alain Laederach2
  • Christopher M Counter4
4 affiliations
  1. 1Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, USA.
  2. 2Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  3. 3Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
  4. 4Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, USA. [email protected].
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Abstract

Synonymous codons occur at unequal rates in the coding genome, with those represented least often termed 'rare.' Rare codon-enriched genes typically exhibit poor expression due to reduced transcription, mRNA stability, export, and translation. However, there are an increasing number of examples whereby rare codon-enriched genes are paradoxically highly expressed, suggestive of mechanisms to overcome the poor expression imposed by rare codons. To identify codon-dependent modifiers, we screen a targeted sgRNA library for genes that, when inactivated, increase the expression of rare versus common codon-enriched fluorescent reporters. This identifies the PAXT connection, a nuclear complex that targets transcripts to the exosome for degradation. Targeted loss of a PAXT component leads to a small but preferential increase in mRNA levels and stability and a more pronounced increase in protein expression of rare compared to common codon-enriched reporters. Transcriptomics coupled to proteomics further reveals that this leads to a preferential increase in the expression of endogenous proteins encoded by poorly expressed and long mRNAs specifically enriched in rare codons. Thus, we identify the PAXT connection as a genetic suppressor of poorly expressed genes enriched in rare codons.

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Cite

BibTeXRIS
BibTeX
@article{niehoff2026paxt,
  title = {{The PAXT connection is a modifier of rare codon-enriched protein expression.}},
  author = {Taylor Niehoff and Jackson Peterson and Siqi Li and Sijin Chen and Christopher V Nicchitta and Alain Laederach and Christopher M Counter},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-77792-7},
  url = {https://europepmc.org/article/MED/42897178},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - The PAXT connection is a modifier of rare codon-enriched protein expression.
AU  - Taylor Niehoff
AU  - Jackson Peterson
AU  - Siqi Li
AU  - Sijin Chen
AU  - Christopher V Nicchitta
AU  - Alain Laederach
AU  - Christopher M Counter
PY  - 2026
DA  - 2026/09/17
JO  - Nature communications
DO  - 10.1038/s41467-026-77792-7
UR  - https://europepmc.org/article/MED/42897178
AB  - Synonymous codons occur at unequal rates in the coding genome, with those represented least often termed 'rare.' Rare codon-enriched genes typically exhibit poor expression due to reduced transcription, mRNA stability, export, and translation. However, there are an increasing number of examples whereby rare codon-enriched genes are paradoxically highly expressed, suggestive of mechanisms to overcome the poor expression imposed by rare codons. To identify codon-dependent modifiers, we screen a targeted sgRNA library for genes that, when inactivated, increase the expression of rare versus common codon-enriched fluorescent reporters. This identifies the PAXT connection, a nuclear complex that targets transcripts to the exosome for degradation. Targeted loss of a PAXT component leads to a small but preferential increase in mRNA levels and stability and a more pronounced increase in protein expression of rare compared to common codon-enriched reporters. Transcriptomics coupled to proteomics further reveals that this leads to a preferential increase in the expression of endogenous proteins encoded by poorly expressed and long mRNAs specifically enriched in rare codons. Thus, we identify the PAXT connection as a genetic suppressor of poorly expressed genes enriched in rare codons.
SN  - 2041-1723
ER  -