DNA is constantly breaking and being repaired in our cells. But what happens when the repair crew itself becomes the obstacle? Our latest study shows that Sae2’s real job is to push one of its partners out of the way, ensuring that repair can continue.
When DNA breaks, it is one of the most serious problems a cell can face. If not repaired properly, these breaks can cause mutations, disease, or even cell death. Cells have evolved sophisticated repair systems, and in yeast one of the key proteins involved is called Sae2. For years, researchers knew that Sae2 worked with another protein, Mre11, during the special type of cell division that makes germ cells. But in normal dividing cells, Sae2’s role was much harder to pin down. Strangely, cells without Sae2 were extremely vulnerable to DNA damage, yet still seemed able to start repairing breaks.
To get to the bottom of this mystery, my team and I used a clever genetic trick. We deleted Sae2 and then searched for other mutations that could “rescue” the cell’s ability to cope with DNA damage. This approach, called synthetic viability screening, led us straight back to Mre11. We discovered that certain changes in Mre11 allowed cells to survive without Sae2.
Looking more closely, we found that the problem in cells lacking Sae2 wasn’t the beginnig of repair but what happened afterward. Without Sae2, Mre11 tended to stay stuck on the broken DNA, physically blocking the next steps of repair. Normally, Sae2 helps clear Mre11 away, freeing the broken DNA ends so the cell’s repair machinery can continue. The rescue mutations in Mre11 made it less likely to jam up the process, explaining why they could bypass the need for Sae2.
This discovery finally resolves a long-standing puzzle about DNA repair. It shows that Sae2’s most important job in dividing cells is not simply to help process DNA, but to ensure that repair proteins don’t linger in the wrong place and hold up the process. Beyond solving this specific mystery, the work highlights the power of genetic screening approaches to reveal hidden roles for key proteins in safeguarding the genome.