Not all DNA follows the classic double helix. Some regions fold into unusual shapes—like G-quadruplexes (G4s), knot-like structures rich in guanine. These “DNA knots” can help regulate gene expression, but if left unresolved, they may damage the genome and contribute to diseases such as cancer. Now, researchers from the lab of Oncode Investigator Puck Knipscheer (Hubrecht Institute), in collaboration with the Karolinska Institutet, have uncovered a surprising mechanism that keeps these structures in check. Their findings, published in Science, reveal an unexpected role for RNA in untangling DNA knots and preserving genome stability.
RNA Joins the Repair Crew
Using extracts from frog eggs—a well-established system for studying DNA replication and repair—the team recreated the untangling process in the lab. They found that when a G4 knot forms, the cell responds as if it were dealing with damaged DNA.
Here’s where it gets interesting: RNA molecules, with help from DNA repair proteins, bind to the strand opposite the G4 and form a structure called a “G-loop.” This loop acts as an intermediate—guiding repair proteins to the right site and helping restore the DNA’s normal double helix shape.
“This was a real surprise,” says first author and Oncode Researcher Koichi Sato. “RNA is mainly known for its role in protein production, but here it plays a crucial role in maintaining genome stability.”
DNA Knots Treated Like Damage
The G-loop doesn’t just facilitate repair—it also triggers the cell’s DNA damage response, even when the DNA isn’t technically broken.
“The cell treats G4s like lesions,” explains Oncode Investigator Puck Knipscheer. “This allows the repair machinery to act quickly—before real damage occurs.”
Thanks to collaborators at the Karolinska Institutet and the lab of Oncode Investigator Alexander van Oudenaarden (Hubrecht Institute), the researchers demonstrated that this mechanism operates across the genome. When it fails, G4s accumulate, block DNA replication, and ultimately cause DNA breaks—stalling cell growth.
Impact: A Potential Weakness in Cancer Cells
Because G4s are especially abundant in cancer cells, the findings could open the door to novel therapeutic strategies. Disrupting the G-loop mechanism—or increasing the formation of G4 structures—might selectively impair cancer cells while sparing healthy ones.
This discovery shines new light on a fundamental DNA repair process and suggests promising ways to target genome instability in cancer.