Researchers at UC San Diego's Skaggs School of Pharmacy have shown that RNA polymerase, the enzyme cells use to transcribe DNA into RNA, can accurately read a synthetic eight-letter genetic alphabet instead of the four letters (A, T, C, G) found in all natural life.
Led by Dong Wang, PhD, the team combined biochemical experiments with high-resolution cryo-electron microscopy, capable of imaging structures smaller than a single atom, to capture RNA polymerase from E. coli recognizing two synthetic base pairs. The enzyme reads these unnatural letters using many of the same structural signals it uses for natural DNA, showing that a cell's existing molecular machinery can process expanded genetic code without modification.
The expanded alphabet, known as "hachimoji" DNA, has already been used experimentally to build synthetic DNA molecules that can recognize liver cancer cells. The new structural findings, published September 2 in Nature Communications, give scientists a molecular blueprint for engineering new diagnostics, therapeutics, and biological systems built on a genetic code richer than nature's own.