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UniProt release 2012_10

Published October 31, 2012


CIA: on your Genome service

Life evolved in an anaerobic world and it is thought that iron-sulfur (Fe-S) clusters played a crucial role in this process by facilitating chemical transformations. Once photosynthesis evolved, oxygen became prevalent, threatening Fe-S clusters as they are susceptible to destruction by oxidation. Despite this potential problem, Fe-S clusters are still cofactors in hundreds of proteins. They are required in virtually all organisms from bacteria to humans and are involved not only in ‘redox’ catalysis in some enzymes, but also in many other functions. Interestingly, Fe-S clusters have been found in many proteins involved in DNA repair and replication and telomere length maintenance.

In eukaryotic cells, most biosynthesis of Fe-S clusters occurs in the mitochondria, but it may also occur in the cytosol and nucleus. In the cytosol, Fe-S clusters are escorted and presented to their cytoplasmic and nuclear apoproteins by the conserved cytoplasmic iron-sulfur assembly (CIA) machinery. However, it is not clear how Fe-S clusters are transferred to target apoproteins, nor how target specificity is achieved.

Two recent and elegant publications have shown that the MMS19 protein is associated with the CIA machinery. This protein also binds a subset of cellular Fe-S proteins, specifically nuclear ones involved in DNA metabolism, including the DNA helicases RTEL1, ERCC2 and ERCC3. MMS19 is required for in vivo incorporation of iron into various DNA repair enzymes and, in the absence of MMS19, cells become more sensitive to DNA damage. The authors suggest that MMS19 functions as a platform to facilitate Fe-S cluster transfer to proteins critical for DNA replication and repair. These experiments point to the importance of Fe-S clusters for the maintenance of genome integrity and imply a central role for mitochondria in genomic DNA metabolism.

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