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The [4Fe4S] cluster of human DNA primase functions as a redox switch using DNA charge transport

O’Brien, Elizabeth and Holt, Marilyn E. and Thompson, Matthew K. and Salay, Lauren E. and Ehlinger, Aaron C. and Chazin, Walter J. and Barton, Jacqueline K. (2017) The [4Fe4S] cluster of human DNA primase functions as a redox switch using DNA charge transport. Science, 355 (6327). Art. No. eaag1789. ISSN 0036-8075. http://resolver.caltech.edu/CaltechAUTHORS:20170223-150518455

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1126/science.aag1789DOIArticle
http://science.sciencemag.org/content/355/6327/eaag1789PublisherArticle
ORCID:
AuthorORCID
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2017 American Association for the Advancement of Science. 19 May 2016; accepted 23 January 2017. Supported by NIH operating grants GM61077 and GM120087 (J.K.B.); NIH operating grants GM65484 and GM118089 (W.J.C.); NIH training grants T32 GM07616 (E.O’B.), T32 GM08230 (M.E.H. and L.E.S.), and T32 CA009582 (A.C.E.); NIH grant S10 RR025677 in support of NMR instrumentation; and the Moore Foundation. Crystallographic data for the p58C Y345F and Y347F mutants have been deposited in the Protein Data Bank under accession numbers PDB 517M and PDB 5DQO, respectively.
Funders:
Funding AgencyGrant Number
NIHGM61077
NIHGM120087
NIHGM65484
NIHGM118089
NIH Predoctoral FellowshipT32 GM07616
NIH Predoctoral FellowshipT32 GM08230
NIH Predoctoral FellowshipT32 CA009582
NIHS10 RR025677
Gordon and Betty Moore FoundationUNSPECIFIED
Record Number:CaltechAUTHORS:20170223-150518455
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20170223-150518455
Official Citation:The [4Fe4S] cluster of human DNA primase functions as a redox switch using DNA charge transport BY ELIZABETH O’BRIEN, MARILYN E. HOLT, MATTHEW K. THOMPSON, LAUREN E. SALAY, AARON C. EHLINGER, WALTER J. CHAZIN, JACQUELINE K. BARTON Science 24 Feb 2017: Vol. 355, Issue 6327, DOI: 10.1126/science.aag1789
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74510
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:23 Feb 2017 23:46
Last Modified:23 Feb 2017 23:55

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