Author SummaryFumarate hydratase (FH; also known as fumarase) is an enzyme found in both the cytoplasm and mitochondria of all eukaryotes. In mitochondria, FH is involved in generating energy for the cell through a metabolic pathway called the Krebs cycle. Its role in the cytoplasm, however, is unclear. FH can function as a tumor suppressor: its absence is linked to the formation of human kidney tumors in a syndrome termed HLRCC. We show here that the cytoplasmic version of FH has an unexpected role in repairing DNA double-strand breaks in the nucleus. This role involves the movement of FH from the cytoplasm into the nucleus and depends on its enzymatic activity. Strikingly, when FH is absent from cells, its function in DNA repair can be substituted by high concentrations of one of the enzyme's products, fumaric acid. Our findings imply that FH deficiency leads to cancer because there is not enough fumaric acid in the nucleus to stimulate repair of DNA double-strand breaks; the persistence of these breaks is believed to provoke cancer. The study thus makes a surprising connection between primary metabolism and the cell's response to DNA damage.