DNA replication actually starts with the synthesis of a short stretch of RNA by the enzyme DNA primase. Extension of the RNA with a similarly short stretch of DNA by DNA polymerase α (pol α) follows before the more efficient and highly processive DNA polymerases take over to finish the job. The mechanisms that regulate the initiation and termination of the RNA primer are poorly understood, but new insight now comes from the work of Vanderbilt Basic Sciences investigator Walter Chazin, his collaborator Jacqueline Barton (California Institute of Techology), and their laboratories. The Chazin and Barton labs focused on an interesting property of DNA – its ability to transfer an electric charge for a long distance along the duplex. They noted that DNA primase, pol α, and a number of other DNA-processing enzymes contain a [4Fe4S] cluster that is readily oxidized and reduced. They hypothesized that charge transfers along DNA could serve as a mechanism for signaling between bound [4Fe4S] cluster-containing proteins, and that this signaling could regulate DNA processing activity. To test their hypothesis, they used a DNA-coated gold electrode to show that the [4Fe4S] cluster of DNA primase is susceptible to direct oxidation and reduction by charge transfer through the DNA duplex. They identified three tyrosine residues that form a charge transfer network between the DNA binding site and the [4Fe4S] cluster of DNA primase, and they showed that interruption of this network led to defects in primer initiation and termination. These findings support the hypothesis that DNA charge transfer, in conjunction with redox centers located within DNA processing enzymes, plays a key role in the regulation of enzyme activity. Further work will seek to define the scope of this interesting new mechanism of enzyme modulation. The work is published in the journal Science [E. O’Brien et al., (2017) Science, 355, eaag1789].