Many DNA-processing enzymes have been shown to contain a 4Fe4S cluster, a common redox cofactor in biology. Using DNA electrochemistry, we find that binding of the DNA polyanion promotes a negative shift in 4Fe4S cluster potential, which corresponds thermodynamically to a ∼500-fold increase in DNA-binding affinity for the oxidized 4Fe4S cluster versus the reduced 4Fe4S cluster. This redox switch can be activated from a distance using DNA charge transport (DNA CT) chemistry. DNA-processing proteins containing the 4Fe4S cluster are enumerated, with possible roles for the redox switch highlighted. A model is described where repair proteins may signal one another using DNA-mediated charge transport as a first step in their search for lesions. The redox switch in eukaryotic DNA primases appears to regulate polymerase handoff, and in DNA polymerase δ, the redox switch provides a means to modulate replication in response to oxidative stress. We thus describe redox signaling interactions of DNA-processing 4Fe4S enzymes, as well as the most interesting potential players to consider in delineating new DNA-mediated redox signaling networks.