Tiny DNA junctions provide feedback to control genetic crossovers

Every new life begins after a genetic shuffle. When organisms make eggs or sperm, maternal and paternal chromosomes pair up and swap pieces of DNA in a process called crossing over. This exchange is essential: without at least one swap per chromosome pair, fertility and healthy chromosome numbers are at risk. At the same time, too many swaps—or too many DNA breaks that initiate them—can harm the genome. How do cells make sure the balance is just right? A team of researchers around Joao Matos of the Max Perutz Labs publishes the answers in Nature.

The team discovered that tiny DNA structures called Holliday junctions are not just stepping-stones on the way to crossovers, as scientists long believed. Instead, they also help stabilize a zipper-like structure known as the synaptonemal complex, which holds paired chromosomes together. This stability, in turn, tells the cell to stop making further DNA breaks, protecting the genome from damage.

Our hypothesis was that Holliday junctions are more than passive DNA links. They are essential for building and maintaining the synaptonemal complex, ensuring that chromosomes stay paired until crossovers are ready to form."

Joao Matos, group leader

To test this idea, first author Adrian Henggeler turned to baker's yeast, a simple organism that scientists often use as a stand-in for human cells because it goes through meiosis in a similar way. He was able to "freeze" millions of yeast cells at the exact moment when the DNA junctions and the chromosome zipper were present, but before the swaps had taken place. By then cutting the DNA junctions using a unique molecular tool developed in the lab, he could see right away what happened next.

"One of our eureka moments was seeing the synaptonemal complex collapse in real time the instant the junctions were removed," says Adrian. "It was exactly what we had hypothesized, suddenly unfolding in front of our eyes." Without Holliday junctions, the chromosome zipper fell apart, new DNA breaks re-started forming, and meiosis could no longer proceed correctly.

"This study uncovers a simple but elegant feedback loop," says Joao. "Once crossovers and the chromosome zipper are stabilized, the cell 'knows' it can stop making breaks and move forward safely with meiosis."

The next challenge is to find out whether the same principle holds true in mammals. If it does, it could shed light on fundamental mechanisms that safeguard fertility and maintain genome stability across species.