An eight - letter alphabet
Chemists have created transcribed synthetic DNA with an eight-letter alphabet
Daria Spasskaya, N+1
American chemists have synthesized four new analogues of nitrogenous bases that form pairs according to the principle of complementarity, just as natural bases A,T,G, C do in the DNA of living organisms. As scientists have shown in an article in Science (Hoshika et al., Hachimoji DNA and RNA: A genetic system with eight building blocks), a polymer containing all eight letters ("hachimoji DNA") resembles ordinary DNA in properties and meets the criteria of an information carrier. Moreover, an RNA molecule was synthesized from an eight-letter matrix using a natural enzyme.
Figure from the press release of Foundation for Applied Molecular Evolution A Synthetic DNA Built from Eight Building Blocks – VM.
The information in the DNA molecules of all living organisms on Earth is encoded using only four letters of the genetic alphabet – A,T,G,C, behind which are hidden nitrogenous bases of purine and pyrimidine type adenine, thymine, guanine and cytosine. These four bases form pairs according to the principle of complementarity (A-T, G-C), which are held by hydrogen bonds. Any sequence of letters forms a double helix of DNA, which has a structure ordered in a certain way.
Erwin Schrodinger, talking about the nature of the information carrier, suggested that it is an atypical crystal, mutations in which do not lead to the loss of the properties of the crystal. The authors of a new article in Science (where Schrodinger is quoted), chemists from the company Firebird Biomolecular Sciences in Florida, led by Steven Benner, one of the pioneers of synthetic biology, expanded the genetic alphabet from four letters to eight. Scientists have shown that the resulting polymer meets the Schrodinger criteria to the same extent as natural DNA. The authors called this polymer "hachimoji DNA", which translates as "eight letters".
Base pairs inside the hachimoji DNA and in the DNA-RNA duplex (from an article in Science).
Scientists synthesized two new pairs, Z-P and S-B, which are also held by hydrogen bonds, and analyzed the properties of a double helix with an expanded alphabet. They showed that such chains have a regular structure and predictable thermodynamic properties regardless of the sequence. In addition, scientists have shown that an RNA chain can be synthesized from the hachimoji matrix.
In this experiment, scientists used a viral T7 RNA polymerase, which synthesized a chain of hachimoji-RNA on a DNA matrix using appropriate ribonucleotides, folding into a specific structure (aptamer). The structure, in turn, bound a fluorescent dye molecule, which was activated at the same time. Thus, the synthesis of RNA could be detected by the glow of the solution.
The structure of the synthesized hachimoji-aptamer RNA and its properties (from an article in Science).
It turned out that the wild-type polymerase is able to use only three new letters out of four, but after going through all the available options, scientists found a mutant version of the polymerase with three amino acid substitutions, which could insert all four new letters into the RNA. Thus, scientists have expanded the genetic alphabet to eight letters, increased the density of encoded information and showed the potential for its decoding in living systems. However, this is not the first such case: we talked about how Floyd Romsberg's group successfully replicated DNA with a six-letter alphabet in bacteria and even encoded new amino acids with it. In this series of works, the scientists used another pair of X-Y, which is held by hydrophobic interactions.
As the creators of hachimoji-DNA write in a new article, hydrophobic interactions impose restrictions on the sequence of letters in which such a pair can be used, because extended sections of such pairs eventually violate the structure of DNA. The authors are still going to use their eight-letter DNA not to expand the genetic code, but for more applied purposes, for example, for bar-coding sequences during sequencing, creating nanostructures with specified properties or for storing information outside the cell (you can read about how DNA is used as an external carrier in our blog).
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