Iron-sulfur cofactors in nucleic acid metabolism and protein synthesis: assembly, delivery, and putative roles in cellular and viral systems

Composed of iron (Fe) and inorganic sulfur (S), iron-sulfur clusters (ISCs) are ancient cofactors present across all domains of life and in some viruses. Over the past three decades, cytosolic and nuclear Fe-S proteins have emerged as integral components of DNA replication and repair machineries, telomere maintenance pathways, transcriptional processes, cell cycle regulation, and protein synthesis. More recently, ISCs were identified in viral proteins, including multiple components of the SARS-CoV-2 replication and transcription complex (RTC), which collectively host seven experimentally verified Fe-S cofactors. The coexistence of multiple ISC-dependent enzymes within both cellular and viral replication machineries raises fundamental questions about how these metal cofactors coordinate genome maintenance, replication, and host-virus interactions. Here, we provide an inventory of known mammalian nucleocytoplasmic Fe-S proteins, discuss mechanisms of ISC acquisition, explore the potential roles of ISCs within cellular and viral replication complexes, and highlight critical gaps in our understanding of ISC delivery, coordination, and function among Fe-S proteins in large multi-subunit assemblies.