Researchers at the University of California, San Diego, have discovered that water molecules play a direct and active role in DNA transcription, overturning the long-held belief that gene expression is driven exclusively by proteins. The findings, published April 30 in the journal Molecular Cell, show that water is an evolutionarily conserved component of the molecular machinery that reads genetic information across all domains of life.

A Hidden Level of Biology

Using cryo-electron microscopy (cryo-EM) capable of resolving structures with an accuracy of less than two angstroms—smaller than the width of a single atom—the research team visualized the inner workings of RNA polymerase II, the enzyme responsible for reading DNA and synthesizing RNA. Through this visualization, scientists were able to identify anywhere from several hundred to over a thousand individual water molecules located at key functional sites of the enzyme.

These water molecules form complex networks that link the enzyme, the DNA, and the incoming RNA building blocks. Rather than acting as passive observers, water molecules actively participate in proton transfer—a key chemical step in adding new nucleotides to the growing RNA chain. They also help the enzyme recognize the correct molecular substrates and stabilize its key structural elements during the transcription process.

Rethinking the Protein-Centric View of Transcription

The study, led by Dong Wang, a professor at the UC San Diego Skaggs School of Pharmacy, and Peijun Zhang, a professor at the University of Oxford, demonstrated that these water networks are evolutionarily conserved—from bacteria to yeast, and likely in humans. The preservation of these structures across such distant branches of the evolutionary tree suggests that water has been an integral part of the transcriptional machinery since its inception. This challenges the traditional "protein-centric" view of gene expression, which researchers now consider outdated.

Implications for Drug Discovery

The results provide a fundamentally new understanding of how genetic information is read and implemented, which could have significant implications for molecular biology, drug development, and the study of disease mechanisms. The paper, titled "Sub-2 Å Cryo-EM Structures of Transcribing RNA Polymerase II Reveal Critical Roles of Water Molecules in Catalysis," was co-authored by researchers from the University of Oxford and the University of Wisconsin-Madison.