Serine tRNAs compete to regulate the mRNA translation of serine-sensitive codons
Differential mRNA translation efficiency (mTE) of codons is important in regulating protein synthesis and cellular states and can change in response to amino acid availability. While the mTE of codons is canonically associated with their corresponding transfer RNA (tRNA) isoacceptors, its regulation by amino acids in mammalian cells remains unexplored. We found that ELAC2, a 3' tRNA maturation endonuclease, decreases the mTE of UC[C/U] serine (Ser) codons in response to Ser limitation. Ablation of ELAC2 restored UC[C/U] mTE but reduced the mTE of AG[U/C] Ser codons. Among the tRNA<sup>Ser</sup> isoacceptors, tRNA<sup>Ser(GCU)</sup> decreased the most in <i>ELAC2</i>-deficient cells. Unexpectedly, tRNA<sup>Ser(GCU)</sup> delivery restored AG[U/C] mTE and reduced UC[C/U] mTE in <i>ELAC2</i>-deficient cells. Last, we deciphered the effects of Ser-sensitive codons on mRNA translation and the human proteome. Our study revealed that in response to Ser limitation, regulation of tRNA<sup>Ser(GCU)</sup> levels fine-tune the mTE of UC[C/U] or AG[U/C] Ser-sensitive codons and shapes the proteome.
Authors
- Robert S. Banh (ORCID: https://orcid.org/0000-0003-1959-4622)
- Alec C. Kimmelman (ORCID: https://orcid.org/0009-0002-9465-8411)
- Beatrix Ueberheide (ORCID: https://orcid.org/0000-0003-2512-0204)
- Veronica Costiniti (ORCID: https://orcid.org/0000-0002-8472-7797)
- Evgeny Kanshin (ORCID: https://orcid.org/0000-0001-7142-4554)
- Wyatt C. Tran (ORCID: https://orcid.org/0009-0002-6162-6261)
- Nandhini Rajesh Babu (ORCID: https://orcid.org/0009-0008-7676-8805)
Institutions
- NYU Langone Health (US)
- New York University (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-11-14
- DOI
- https://doi.org/10.1126/sciadv.ady4521
- Citations
- 1
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Institutes of Health
- Stand Up To Cancer