Emerging critical roles of Fe–S clusters in DNA replication and repair

Abstract

Fe-S clusters are partners in the origin of life that predate cells, acetyl-CoA metabolism, DNA, and the RNA world. The double helix solved the mystery of DNA replication by base pairing for accurate copying. Yet, for genome stability necessary to life, the double helix has equally important implications for damage repair. Here we examine striking advances that uncover Fe-S cluster roles both in copying the genetic sequence by DNA polymerases and in crucial repair processes for genome maintenance, as mutational defects cause cancer and degenerative disease. Moreover, we examine an exciting, controversial role for Fe-S clusters in a third element required for life – the long-range coordination and regulation of replication and repair events. By their ability to delocalize electrons over both Fe and S centers, Fe-S clusters have unbeatable features for protein conformational control and charge transfer via double-stranded DNA that may fundamentally transform our understanding of life, replication, and repair.

Compartmentalization of iron between mitochondria and the cytosol and its regulation

“…The maturation of extra-mitochondrial proteins requires the export of a small solute that is produced by the mitochondrial ISC system and exported via the mitochondrial ABC transporter Atm1 into the cytosol where it is used by the cytosolic Fe/S protein assembly (CIA) system for the formation of cytosolic and nuclear Fe/S proteins (Lill et al, 2014a;Netz et al, 2014;Paul and Lill, 2015;Sharma et al, 2010). Several cytosolic and nuclear Fe/S proteins play essential roles in protein translation (e.g., the ABC protein Rli1) (Hopfner, 2012), DNA synthesis and repair (e.g., DNA polymerases and helicases) (Fuss et al, 2015;White, 2009), and other aspects of genome stability (Gari et al, 2012;Lill et al, 2014b;Stehling et al, 2012;Wu and Brosh, 2012). Hence, many of the 17 known members of the mitochondrial ISC systems are essential for cell viability, and mutations in genes encoding ISC members are associated with recessive diseases with complex neurodegenerative, hematological and metabolic phenotypes (Beilschmidt and Puccio, 2014;Rouault, 2012;.…”

The Oxidation State of [4Fe4S] Clusters Modulates the DNA-Binding Affinity of DNA Repair Proteins

“…5,6 An increasing number of DNA-processing enzymes, including many that are involved in the repair of DNA damage, have been found in archaea, bacteria, and eukaryotes to contain [4Fe4S] clusters. 7–10 Elucidating the role of these clusters remains an active area of investigation. 11–14 Initially, these clusters were proposed to serve primarily a role in maintaining protein structural integrity.…”

The Yeast Nbp35-Cfd1 Cytosolic Iron-Sulfur Cluster Scaffold Is an ATPase

“…The growing number of DNA replication and repair enzymes requiring an FeS cluster for their function and the recent discovery that defects in de novo cluster biogenesis result in genomic instability have sparked interest in elucidating how FeS enzymes located within the nucleus acquire their cofactor (1,2). Currently eight proteins have been identified as components of the eukaryotic cytosolic iron sulfur cluster assembly (CIA) 3 pathway required for maturation of cytosolic and nuclear, but not mitochondrial, FeS enzymes (3).…”

“…The authors declare that they have no conflicts of interest with the contents of this article. 1 Supported by the Boston University Undergraduate Research Opportunities Program. 2 To whom correspondence should be addressed: Dept.…”