At the ends of our chromosomes lie telomeres, repetitive DNA sequences that protect our genetic material like the plastic tips on shoelaces. Within these telomeric regions, unusual four-stranded DNA structures called G-quadruplexes can form, playing important roles in genome stability. Now, researchers have resolved the atomic-resolution structure of a previously elusive hybrid form of this structure, one built from both DNA and RNA strands together.

A research team at the Hefei Institutes of Physical Science, Chinese Academy of Sciences, led by Prof. Zhang Na at the High Magnetic Field Laboratory, has determined the first atomic-resolution structure of an RNA-DNA hybrid G-quadruplex (RDQ) formed between a human telomeric DNA sequence and a fragment of TERRA, a long non-coding RNA transcribed from telomeric regions. The findings are published in the Journal of the American Chemical Society.

An Atypical Structural Discovery

Using nuclear magnetic resonance (NMR) spectroscopy, the team resolved the three-dimensional architecture of the hybrid quadruplex, revealing a (3+1) mixed strand orientation in which three DNA strands and one RNA strand come together in an unusual arrangement. Central to the discovery was the identification of a guanine ribonucleotide within the RNA strand that adopts a syn glycosidic conformation, an atypical structural state for RNA guanines that had not been previously characterized in this context.

The researchers found that formation of this hybrid RNA-DNA quadruplex structure appears to protect both the DNA and RNA strands from degradation. Because TERRA RNA is transcribed directly from telomeric DNA, the two strands are complementary and could otherwise pair up in ways that leave the genetic material vulnerable. The RDQ structure may instead help separate matching DNA and RNA strands from one another, a mechanism the researchers suggest could play a role in maintaining telomere protection and overall genome stability.

Telomere dysfunction is closely linked to aging and cancer, as the gradual shortening of telomeres over successive cell divisions is a hallmark of cellular aging, while telomere maintenance mechanisms are frequently hijacked by cancer cells to achieve unlimited replication. Structural insights into how DNA and RNA interact at telomeres, such as this newly resolved hybrid quadruplex, could inform future strategies for understanding and potentially targeting these processes.

The work adds to a growing body of research into G-quadruplex structures, which have drawn increasing scientific interest not only for their roles in telomere biology but also as potential targets for therapeutic intervention in cancer and other diseases linked to genomic instability.

Journal: Journal of the American Chemical Society
Article Title: A Guanine Ribonucleotide Atypically Adaptive to the Syn Glycosidic Conformation in a Human Telomeric DNA–TERRA RNA Hybrid G-Quadruplex with (3 + 1) Mixed Strand Orientations Studied by NMR
Publication Date: 25-Jun-2026