Science 337, 195–199 (2012)

Science 337, 243–245 (2012)

Iron-sulfur (Fe-S) clusters are produced in mitochondria and then exported via a cascade of proteins to the cytosolic iron-sulfur protein assembly (CIA) pathway, but how nascent Fe-S clusters are delivered to their target proteins remains unclear. Two studies identify MMS19 as a component of the CIA machinery that delivers Fe-S clusters to proteins that maintain genomic integrity. In parallel studies involving yeast and human cell lines, Stehling et al. and Gari et al. used proteomic and 55Fe-labeling experiments to show that MMS19 binds key components of the CIA complex in the cytoplasm and acts late during Fe-S cluster biogenesis. Both groups further showed that MMS19 is required for the maturation of a subset of Fe-S proteins, all of which had roles in DNA metabolism. Stehling et al. demonstrated that MMS19-deficient cells were hypersensitive to genotoxic agents and had elevated DNA damage responses. Gari et al. showed that MMS19 deficiency lowered the stability of nuclear Fe-S target proteins in cells, and Mms19 knockout mice had an embryonic lethal phenotype. Taken together, these studies explain previously observed effects of Mms19 mutations, provide a model for how Fe-S clusters may be transferred to subpopulations of the proteome and open the search for other similar adaptor proteins.