![]() Translation using quadruplet codons exists in both natural and synthetic systems, so why did nature favor a triplet system overall? Now, in eLife, Erika DeBenedictis, Dieter Söll and Kevin Esvelt at the Massachusetts Institute of Technology and Yale University, report how tRNAs can be evolved to read quadruplet codons more efficiently ( DeBenedictis et al., 2022). Heinemann, Patrick O’Donoghue (CC BY 4.0). The work represents an important step towards engineering a quadruplet genetic code with 256 codons. Next, tRNAs were evolved through various mutations into more effective quadruplet-decoding tRNAs (qtRNAs, purple dots, right). then recorded the translation efficiency of tRNAs with simple mutations to expand the anticodon loop (middle, red dots). The ability of a particular tRNA variant to read that +1-frameshift mutation as a four-base codon can be measured as a function of how much full length and active reporter protein (e.g., luciferase) is made in cells. created reporter genes (such as luciferase) with a single base insertion (also referred to as +1 frameshift). To test the efficiency of four-base translation, DeBenedictis et al. to evolve triplet-decoding tRNAs (left) into tRNAs with expanded anticodon loops (red dots) to decode quadruplet codons consisting of four nucleotide bases (N middle), and ultimately into efficient quadruplet codon decoders (right). The schematic illustrates the approach used by DeBenedictis et al. A tRNA that suppresses a +1 frameshift effectively reads or decodes a quadruplet codon ( Figure 1). For example, some tRNAs can read frameshift mutations, including insertions or deletions of one or two nucleotides in the mRNA. So-called frameshift suppressor tRNAs allow protein synthesis to continue past this insertion to produce a normal full-length protein. The insertion of a single base generates a frameshift in an otherwise triplet codon gene, shifting the frame by one letter. One approach to expanding the genetic code is based on a natural process called +1 frameshifting, where four rather than three nucleotide bases are effectively decoded as a single amino acid ( Riyasaty and Atkins, 1968). Expanding the number of protein building blocks would help to produce highly specialized proteins containing unnatural amino acids, potentially opening the door to advances in both basic biology and therapeutic applications ( Hohsaka et al., 1996). Reassigning a codon to a new amino acid would drastically change the organisms’ protein composition.Ī quadruplet system based on four-letter codons rather than three has 256 total codons that could encode many more amino acids, independent of the natural triplet codon system. However, the standard triplet codons cannot be easily reassigned into new amino acids, because even though decoding the 64 codons allows for redundancy, all codons are assigned to a specific amino acid in an organism. Recent engineering efforts have successfully produced proteins using 22 or even 23 different amino acids, rather than the usual 20 ( Wright et al., 2018 Tharp et al., 2021). Despite this wealth of codons, most organisms usually use just 20 amino acids, making the code redundant as several codons can code for the same amino acid.Įxpanding or modifying the genetic code may enable scientists to use cells as factories for making an array of molecules, which could further therapies based on proteins, and in even grander schemes, to enable the creation of artificial life forms. On the ribosome, molecules known as transfer RNAs (tRNAs) decode the information in mRNAs by reading it in three-letter groups, also known as codons, allowing for 64 unique triplet combinations (three of which are used as stop signals). Some segments of the DNA genome are instructions for making proteins, and a messenger RNA molecule (mRNA) is produced from the DNA template for each protein-coding gene. DNA molecules are chain-like structures consisting of two entwined strands that encode information using an ‘alphabet’ of four nucleotide building blocks (made up of a sugar and a phosphate group, and one of four nitrogenous bases, A, C, G and T). Cells use a genetic code to translate the information contained in DNA and RNA sequences into the amino-acid building blocks that make up a protein ( Nirenberg et al., 1965 Söll et al., 1965).
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