Why Mutant Mice and Their DNA Repair

Scientists recently found that DNA ligase 4 (Lig4) plays a crucial role in fixing broken DNA, even if it can't directly stick the pieces back together. They created mice with a mutation in Lig4, making it inactive. Surprisingly, these mice were born alive, but they weren't growing properly and had trouble with their immune cells. This suggests the inactive Lig4 was still helping out in some way. But when these mice didn't have another repair protein, called nuclear Lig3, they couldn't survive. This shows that Lig3 might be stepping in when Lig4 is out of commission, helping to fix broken DNA.First, scientists studied how Lig4 works in cells. They discovered that even when Lig4 can't do its job, it can still bring other repair proteins to the scene. This is important for a process called non-homologous end joining (NHEJ), which fixes big DNA breaks. They then made mice with a mutation in Lig4's active site, expecting them to be sick, but they were born alive. These mice were smaller and had issues with their immune system, but they were alive, hinting that Lig4 might have other jobs besides fixing DNA. Next, they looked at mice missing nuclear Lig3. These mice were smaller and had some issues with fluid buildup in their brains, but otherwise seemed normal. When they crossed these mice with the Lig4 mutant mice, something unexpected happened. No mice with both mutations were born. Careful timing of when the pregnant mice gave birth revealed that the fetuses with both mutations were being reabsorbed, meaning they couldn't grow properly in the womb. This led to a crucial finding: Lig3 might be helping out in DNA repair complexes when Lig4 is there but not doing its usual job.