During meiosis, the highly conserved synaptonemal complex (SC) mediates the synapsis of homologous chromosomes, to allow for genetic exchange and crossing over. Crossing over is the process during meiosis in which the maternal and paternal chromosomes exchange homologous DNA segments, creating new genetic combinations. Accuracy is critical: to ensure stable chromosome numbers, every chromosome pair must undergo at least one crossover event, but too many double strand breaks could result in DNA damage. Precisely how SC formation is initiated and maintained during this delicate process is still unknown. Using yeast as a model system, the Matos lab now demonstrates that Holliday junctions – intermediate four-way DNA structures formed prior to crossover formation – play a central role in stabilizing the SC and suppressing new double strand break formation.
“Our hypothesis was that Holliday junctions are more than passive DNA links”, explains group leader Joao Matos. “They are essential for building and maintaining the synaptonemal complex, ensuring that chromosomes stay paired until crossovers are ready to form”. The junctions arise after cells intentionally create double-strand breaks, which help homologous chromosomes find and pair with each other. As the zipper-like synaptonemal complex forms, it signals the cell to stop making new breaks, preventing excessive DNA damage. Without Holliday junctions, the team speculated that the SC would collapse.
To test the hypothesis, first author Adrian Henggeler designed a powerful experimental system in yeast. Adrian was able to ‘freeze’ millions of yeast cells at the exact moment when the SC and Holliday junctions had assembled, but before crossovers had taken place. By cutting the DNA junctions using a unique molecular tool developed in the lab, he could see right away what happened next. The results were striking. Adrian recalls: “One of our eureka moments was watching in real time as the synaptonemal complex collapsed the moment the junctions were cut – it was exactly what we had hypothesized, now happening in front of our eyes.” Without Holliday junctions, the chromosome zipper fell apart, new DNA breaks formed, and meiosis could no longer proceed correctly.
Meiosis-specific ZMM proteins are known to bind and stabilize DNA double-strand repair intermediates, but their role in maintaining Holliday junctions and controlling new break formation had not been shown. The Matos lab also demonstrated that these proteins work together with Holliday junctions to maintain the synaptonemal complex and suppress additional double-strand breaks. Joao explains: “This study reveals a simple but elegant feedback loop: once the chromosome zipper is stabilized, the cell ‘knows’ it can stop making DNA breaks and can safely move on with meiosis.”
Looking ahead, the team will test whether this mechanism is evolutionarily conserved by studying SC assembly during meiosis in mammals. Ultimately, the Matos lab hopes to understand how meiosis promotes genetic diversity while simultaneously safeguarding genome stability.
DOI: 10.1038/s41586-025-09559-x