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Redox Chemistry in the Genome: Emergence of the [4Fe4S] Cofactor in Repair and Replication

Barton, Jacqueline K. and Silva, Rebekah M. B. and O'Brien, Elizabeth (2019) Redox Chemistry in the Genome: Emergence of the [4Fe4S] Cofactor in Repair and Replication. Annual Review of Biochemistry, 88 . pp. 163-190. ISSN 0066-4154. PMCID PMC6590699. doi:10.1146/annurev-biochem-013118-110644.

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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]^(3+) cluster versus the reduced [4Fe4S]^(2+) 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.

Item Type:Article
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URLURL TypeDescription CentralArticle
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2019 by Annual Reviews. We are grateful to the NIH (grant GM126904) for their continued financial support and to our many coworkers and collaborators in elucidating this chemistry. The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.
Funding AgencyGrant Number
Subject Keywords:DNA charge transport, iron–sulfur clusters, base excision repair, DNA primase, DNA polymerase, redox signaling, oxidative stress
PubMed Central ID:PMC6590699
Record Number:CaltechAUTHORS:20190624-083057369
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Official Citation:Redox Chemistry in the Genome: Emergence of the [4Fe4S] Cofactor in Repair and Replication. Jacqueline K. Barton, Rebekah M.B. Silva, Elizabeth O'Brien. Annual Review of Biochemistry 2019 88:1, 163-19; doi: 10.1146/annurev-biochem-013118-110644
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:96654
Deposited By: Tony Diaz
Deposited On:24 Jun 2019 17:06
Last Modified:16 Nov 2021 17:22

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