UC San Diego Study Demonstrates RNA Polymerase Transcription of Eight-Letter Genetic Alphabet

Structural Breakthrough in Expanded Synthetic Genetics

Researchers at the University of California San Diego have demonstrated that bacterial RNA polymerase, a key cellular enzyme responsible for transcribing DNA into RNA, can read and transcribe an expanded genetic alphabet consisting of eight letters.

All known naturally occurring terrestrial organisms rely on a four-letter genetic system. The new findings demonstrate that standard cellular machinery can process non-natural genetic information, advancing long-standing efforts in synthetic biology to build expanded genetic systems.

Molecular Imaging and Enzyme Mechanics

To analyze how the enzyme interacts with non-natural genetic codes, the research team combined biochemical assays with high-resolution cryo-electron microscopy (cryo-EM) to map structural configurations at sub-atomic scales.

The structural data captured RNA polymerase from Escherichia coli (E. coli) as it recognized and incorporated two synthetic base pairs. The images indicated that the enzyme relies on structural and biochemical signaling pathways similar to those used when transcribing naturally occurring base pairs.

Companion Research on Unnatural Base Pairs

The study, titled "Structural Basis of Transcription of the Hachimoji Eight-Letter Alphabet by E. coli RNA Polymerase," was led by Dr. Dong Wang, a professor at the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, and published on September 2, 2026, in Nature Communications.

In a related study published in the Proceedings of the National Academy of Sciences (PNAS), the research team observed that E. coli RNA polymerase can also recognize another set of synthetic base pairs that lack traditional hydrogen bonding. Despite the absence of hydrogen bonds, the hydrophobic unnatural base pairs successfully promoted trigger loop closure and catalytic activity within the enzyme.

Industrial and Therapeutic Relevance

Expanded genetic codes have previously been utilized in research to synthesize custom DNA molecules capable of identifying liver cancer cells. By establishing the structural parameters required for enzymatic transcription of synthetic letters, the findings provide a framework for future applications in synthetic biology, diagnostics, and novel therapeutic development.