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Review
. 2024 May 10:15:1420331.
doi: 10.3389/fgene.2024.1420331. eCollection 2024.

Suppressor tRNAs at the interface of genetic code expansion and medicine

Aya Awawdeh #  1 , Alexander A Radecki #  1 , Oscar Vargas-Rodriguez  1
Affiliations
Review

Suppressor tRNAs at the interface of genetic code expansion and medicine

Aya Awawdeh et al. Front Genet. .

Abstract

Suppressor transfer RNAs (sup-tRNAs) are receiving renewed attention for their promising therapeutic properties in treating genetic diseases caused by nonsense mutations. Traditionally, sup-tRNAs have been created by replacing the anticodon sequence of native tRNAs with a suppressor sequence. However, due to their complex interactome, considering other structural and functional tRNA features for design and engineering can yield more effective sup-tRNA therapies. For over 2 decades, the field of genetic code expansion (GCE) has created a wealth of knowledge, resources, and tools to engineer sup-tRNAs. In this Mini Review, we aim to shed light on how existing knowledge and strategies to develop sup-tRNAs for GCE can be adopted to accelerate the discovery of efficient and specific sup-tRNAs for medical treatment options. We highlight methods and milestones and discuss how these approaches may enlighten the research and development of tRNA medicines.

Keywords: RNA therapeutics; genetic code expansion; nonsense mutations; premature termination codons; synthetic biology; tRNA; translation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

FIGURE 1
FIGURE 1
tRNA structure. (A) Secondary (cloverleaf) structure. The anticodon and elongation factor’s recognition bases are numbered. Bases 37 and 38 are known to increase PTC translation. (B) Tertiary (L-shaped) structure. (A,B) were created with BioRender.com and the tRNA crystal structure (PDB:1EVV), respectively.
FIGURE 2
FIGURE 2
Mechanistic differences and requirements between canonical, PTC, and GCE translation. For GCE translation, an orthogonal tRNA-aaRS pair is required. The orthogonal pair does not interact with endogenous tRNAs and aaRSs. The orthogonality requirement is achieved by introducing a tRNA-aaRS pair from an organism distinct from the host species. Created with BioRender.com.
See this image and copyright information in PMC

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