Several important anti-cancer drugs kill cells by linking their DNA together with chemical bonds to form crosslinks. However, cancer cells may repair crosslinks and thus survive treatment. We want to understand how this protection occurs. In this grant, we propose to study an enzyme called Mus81-Emel that acts as a 'molecular pair of scissors' that cuts certain forms of DNA. We know that this 'cutting' action is important for repairing crosslinks because mice or cells missing Mus81-Emel are more sensitive to anti-cancer drugs that cause crosslinks. Importantly, these mice are very cancer-prone, which tells us that this 'cutting' action also protects against cancer. Mice missing Mus81 are very similar to patients with Fanconi anemia, so we want to understand how Mus81-Emel relates to proteins that are defective in patients with the disease.