G-quadruplexes are special structures formed by guanine-rich DNA or RNA sequences. RNA–DNA hybrid G-quadruplexes (RDQs), which are formed between RNA and DNA strands, have attracted increasing attention because they may play important roles in genome stability and regulation. However, due to the lack of high-resolution structural information, their biological functions remain poorly understood.

In a study published in Journal of the American Chemical Society, a research team led by Prof. ZHANG Na from the Hefei Institutes of Physical Science of the Chinese Academy of Sciences determined the first atomic-resolution structure of a RDQ formed between human telomeric DNA and a telomeric repeat-containing RNA (TERRA) RNA fragment.

Researchers used solution nuclear magnetic resonance (NMR) spectroscopy to determine the detailed structure of an RDQ formed by a three-repeat human telomeric DNA sequence and a short fragment of TERRA. The structure revealed that DNA and RNA strands can assemble into a unique arrangement, with both parallel and antiparallel strand orientations.

Besides, researchers discovered that one RNA guanine residue in the RDQ adopts an unusual structural state that is rarely observed in RNA G-quadruplexes, which shows that RNA molecules can adjust their structures when interacting with DNA, expanding the understanding of how RNA–DNA hybrid structures form.

Further experiments showed that RDQ formation can protect both DNA and RNA strands from degradation. Researchers also found that longer RNA molecules and their shorter fragments can work together to promote the separation of matching DNA strands, suggesting that RDQs may participate in regulating interactions between RNA and DNA in cells.

The findings of this study improve the understanding of RDQs and their possible roles in protecting telomeres and maintaining genome stability.