Abstract
This year marks the 48th anniversary of Francis Crick’s seminal work on the origin of the genetic code, in which he first proposed the “frozen accident” hypothesis to describe evolutionary selection against changes to the genetic code that cause devastating global proteome modification. However, numerous efforts have demonstrated the viability of both natural and artificial genetic code variations. Recent advances in genetic engineering allow the creation of synthetic organisms that incorporate noncanonical, or even unnatural, amino acids into the proteome. Currently, successful genetic code engineering is mainly achieved by creating orthogonal aminoacyl-tRNA/synthetase pairs to repurpose stop and rare codons or to induce quadruplet codons. In this review, we summarize the current progress in genetic code engineering and discuss the challenges, current understanding, and future perspectives regarding genetic code modification.
Highlights
In 1968, Francis Crick first proposed the frozen accident theory of the genetic code [1]
Some existing noncanonical amino acids (NCAAs) are known to be compatible with enzymatic aminoacylation [12,13,14,15,16,17,18,19,20], the 20 canonical amino acids in the standard genetic code have been stringently selected over the course of biological evolution
Might cooperatively increase 4-FTrp uptake, similar to the effect of Trp operon RNA-binding attenuation protein (TRAP) knockout in B. subtilis. These findings suggest that an efficient NCAA uptake system is essential to accommodation of the modified genetic codes
Summary
In 1968, Francis Crick first proposed the frozen accident theory of the genetic code [1]. NCAAs can be artificially incorporated in a site-specific or proteome-wide manner In the former, scientists have attempted to artificially engineer organisms for compatibility with various NCAAs by employing orthogonal tRNA/aminoacyl-tRNA synthetase pairs [28,29,30,31,32]. Researchers are recording cellular responses and genetic changes in engineered organisms to understand the mechanisms behind the use of alternative genetic codes. We first give a brief introduction of current studies on both site-specific and proteome-wide incorporation of NCAAs. we will focus on the challenges of engineering organisms to use modified genetic codes and their implications, such as inhibitory effects caused by NCAAs. we will discuss current trends in this research area
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