title: The [4Fe4S] cluster of human DNA primase functions as a redox switch using DNA charge transport.
abstract: DNA charge transport chemistry offers a means of long-range, rapid redox signaling. We demonstrate that the [4Fe4S] cluster in human DNA primase can make use of this chemistry to coordinate the first steps of DNA synthesis. Using DNA electrochemistry, we found that a change in oxidation state of the [4Fe4S] cluster acts as a switch for DNA binding. Single-atom mutations that inhibit this charge transfer hinder primase initiation without affecting primase structure or polymerization. Generating a single base mismatch in the growing primer duplex, which attenuates DNA charge transport, inhibits primer truncation. Thus, redox signaling by [4Fe4S] clusters using DNA charge transport regulates primase binding to DNA and illustrates chemistry that may efficiently drive substrate handoff between polymerases during DNA replication.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Elizabeth
authors.identifier: 0000-0003-2889-1688
authors.initials: E
authors.lastname: O'Brien
authors.affiliation: Departments of Biochemistry and Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Marilyn E
authors.identifier: 0000-0002-3164-869X
authors.initials: ME
authors.lastname: Holt
authors.affiliation: Departments of Biochemistry and Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Thompson
authors.affiliation: Departments of Biochemistry and Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Lauren E
authors.identifier: 0000-0001-8513-1891
authors.initials: LE
authors.lastname: Salay
authors.affiliation: Departments of Biochemistry and Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Aaron C
authors.identifier: 0000-0003-2036-7355
authors.initials: AC
authors.lastname: Ehlinger
authors.affiliation: Departments of Biochemistry and Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN 37235, USA. jkbarton@caltech.edu walter.j.chazin@vanderbilt.edu.
authors.forename: Walter J
authors.identifier: 0000-0002-2180-0790
authors.initials: WJ
authors.lastname: Chazin
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA. jkbarton@caltech.edu walter.j.chazin@vanderbilt.edu.
authors.forename: Jacqueline K
authors.identifier: 0000-0001-9883-1600
authors.initials: JK
authors.lastname: Barton
mesh_terms: D001692:Biological Transport; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism*; D019915:DNA Primase / Q000737:chemistry* / Q000235:genetics; D004261:DNA Replication; D004572:Electrolysis; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000737:chemistry* / Q000235:genetics; D009154:Mutation; D010084:Oxidation-Reduction; D058105:Polymerization; D011485:Protein Binding; D000072417:Protein Domains
chemical_list: D007506:Iron-Sulfur Proteins; D004247:DNA; D019915:DNA Primase