Eight

The discovery of E. coli RNA polymerase accurately reading and transcribing an expanded, eight-letter genetic alphabet has significant implications for synthetic biology. This finding provides evidence that cells can process synthetic genetic information using their natural molecular machinery.

Researchers at the University of California San Diego have demonstrated that one of biology's most essential enzymes can read and transcribe a synthetic genetic alphabet. The expansion from four letters to eight letters is a crucial step in gene expression, as it allows for the creation of new genetic code that can be used in various applications.

The study published in Nature Communications focused on RNA polymerase, the enzyme responsible for reading DNA and producing RNA. Using biochemical experiments and high-resolution cryo-electron microscopy, researchers captured detailed structural snapshots showing how RNA polymerase recognizes and incorporates synthetic base pairs. These snapshots revealed that the enzyme recognizes synthetic DNA letters through the same biochemical and structural signals as natural base pairs.

The implications of this work extend beyond basic biology. Previous studies have used expanded genetic alphabets to create synthetic DNA molecules capable of recognizing liver cancer cells. By revealing how RNA polymerase accurately reads and transcribes these non-natural DNA letters, the new study provides a molecular foundation for future technologies that use expanded genetic codes.

Structural Basis of Transcription of the Hachimoji Eight-Letter Alphabet by E. coli RNA Polymerase

This work has significant implications for various fields, including medicine, agriculture, and biotechnology. The ability to create synthetic DNA molecules with specific base pairs will enable the development of new diagnostic tools and therapeutics.

Qingrong Li et al, Hydrophobic unnatural base pair promotes trigger loop closure and catalysis in cellular RNA polymerase independent of hydrogen bonding, Proceedings of the National Academy of Sciences (2026). DOI: 10.1073/pnas.2607774123

The discovery of E. coli RNA polymerase accurately reading and transcribing a synthetic genetic alphabet is a significant milestone in the field of synthetic biology. This work has far-reaching implications for various applications, including medicine and biotechnology.

Journal information: Proceedings of the National Academy of Sciences , Nature Communications