Iron-Sulfur Cluster Dynamics in DNA Repair and Replication

Iron–sulfur (Fe–S) clusters are evolutionarily conserved cofactors that support an array of DNA replication and repair enzymes. These clusters not only stabilise protein structure but also enable redox chemistry that can modulate enzymatic activity in response to cellular and environmental cues. Biosynthesis of Fe–S clusters begins in the mitochondrion and culminates in the cytosol, where the late‐acting cytosolic iron–sulfur assembly (CIA) complex delivers mature [4Fe–4S] clusters to nuclear targets. Recipient proteins span DNA glycosylases, helicases, primases and polymerases, all of which require precise cluster insertion for optimal function. During base excision repair, for example, redox‐active clusters facilitate lesion recognition and strand incision, whereas in replication, they act as sensors of oxidative or replication stress, adjusting polymerase and helicase activities accordingly. Emerging evidence also highlights DNA‐mediated charge transport as a conduit for inter‐enzyme communication, allowing distant Fe–S‐containing proteins to exchange electrons along the DNA duplex. Together, these findings underscore a dynamic network in which Fe–S cluster assembly, insertion and redox cycling are integral to genome maintenance and cellular homeostasis.

Research from Nature Portfolio

Recent studies have employed a combination of far‐infrared and mid‐infrared spectromicroscopy alongside density functional theory to investigate the [4Fe–4S] cluster of Endonuclease III. Upon binding double-stranded DNA, characteristic vibrational modes of Fe–S(sulfide) and Fe–S(thiolate) bonds shift, revealing bond‐length alterations that favour a higher oxidation state. These structural adjustments stabilise the cluster against oxidative degradation and facilitate rapid redox communication between the glycosylase and other repair factors through the DNA helix. The work provides a mechanistic framework for how DNA binding dynamically tunes cluster properties during base excision repair.

Iron-Sulfur Cluster Dynamics in DNA Repair and Replication publication trend

The graph below shows the total number of articles in iron-sulfur cluster dynamics in dna repair and replication across all publications each year (not limited to Nature Index journals).

Technical terms

Iron–sulfur (Fe–S) cluster: A metal cofactor composed of iron and inorganic sulphide atoms, critical for electron transfer and structural integrity in proteins.

Cytosolic iron–sulfur assembly (CIA) complex: A multiprotein machinery responsible for the maturation and delivery of [4Fe–4S] clusters to cytosolic and nuclear target proteins.

Base excision repair (BER): A DNA repair pathway that recognises and removes damaged bases, creating abasic sites subsequently processed by specialised endonucleases and polymerases.

DNA-mediated charge transport (DNA CT): A mechanism by which electrons can move along the π-stacked base pairs of the DNA duplex, enabling redox communication between distantly bound proteins.

Redox signalling: Modulation of protein function through reversible oxidation and reduction of redox‐active cofactors, such as Fe–S clusters, in response to cellular signals.

References

1. A combined Far-FTIR, FTIR Spectromicroscopy, and DFT Study of the Effect of DNA Binding on the [4Fe4S] Cluster Site in EndoIII. Scientific Reports (2020).
2. Maintenance of genome integrity by the late-acting cytoplasmic iron-sulfur assembly (CIA) complex. Frontiers in Genetics (2023).
3. The [4Fe4S] Cluster of Yeast DNA Polymerase ε Is Redox Active and Can Undergo DNA-Mediated Signaling. Journal of the American Chemical Society (2021).