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DNA-Mediated Signaling by Proteins with 4Fe−4S Clusters Is Necessary for Genomic Integrity

Grodick, Michael A. and Segal, Helen M. and Zwang, Theodore J. and Barton, Jacqueline K. (2014) DNA-Mediated Signaling by Proteins with 4Fe−4S Clusters Is Necessary for Genomic Integrity. Journal of the American Chemical Society, 136 (17). pp. 6470-6478. ISSN 0002-7863. PMCID PMC4017601. doi:10.1021/ja501973c.

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Iron–sulfur clusters have increasingly been found to be associated with enzymes involved in DNA processing. Here we describe a role for these redox clusters in DNA-mediated charge-transport signaling in E. coli between DNA repair proteins from distinct pathways. DNA-modified electrochemistry shows that the 4Fe–4S cluster of DNA-bound DinG, an ATP-dependent helicase that repairs R-loops, is redox-active at cellular potentials and ATP hydrolysis increases DNA-mediated redox signaling. Atomic force microscopy experiments demonstrate that DinG and Endonuclease III (EndoIII), a base excision repair enzyme, cooperate at long-range using DNA charge transport to redistribute to regions of DNA damage. Genetics experiments, moreover, reveal that this DNA-mediated signaling among proteins also occurs within the cell and, remarkably, is required for cellular viability under conditions of stress. Silencing the gene encoding EndoIII in a strain of E. coli where repair by DinG is essential results in a significant growth defect that is rescued by complementation with EndoIII but not with an EndoIII mutant that is enzymatically active but unable to carry out DNA charge transport. This work thus elucidates a fundamental mechanism to coordinate the activities of DNA repair enzymes across the genome.

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Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2014 American Chemical Society. ACS AuthorChoice. Received: February 25, 2014. Publication Date (Web): April 16, 2014. We are grateful to the NIH (GM49216), the Moore Foundation (Caltech Signaling Center), and the Center for Environmental Microbial Interactions (CEMI, Caltech) for their financial support. M.A.G. and H.M.S. were NIH predoctoral trainees (NIH/NRSA 5T32GM07616) and T.J.Z. an NSF fellow (DGE-1144469). We are also grateful to the Beckman Institute MMRC for AFM instrumentation. We thank Dr. Huangen Ding (Louisiana State University, Baton Rouge, LA) for helpful discussions regarding DinG, the Coli Genetic Stock Center (CGSC, Yale) for distributing the BW16847 and JW1625-1, and Dr. B. Michel (Gif-sur-Yvette) for the gift of the InvA bacterial strain and RNaseH overexpression plasmid. Lastly we thank Ms. Janani Comar for research assistance. The authors declare no competing financial interest.
Group:Caltech Center for Environmental Microbial Interactions (CEMI)
Funding AgencyGrant Number
Caltech Signaling CenterUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
Caltech Center for Environmental Microbial Interactions (CEMI)UNSPECIFIED
NIH Predoctoral Fellowship5T32GM07616
NSF Graduate Research FellowshipDGE-1144469
Issue or Number:17
PubMed Central ID:PMC4017601
Record Number:CaltechAUTHORS:20140422-093606577
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Official Citation:DNA-Mediated Signaling by Proteins with 4Fe–4S Clusters Is Necessary for Genomic Integrity Michael A. Grodick, Helen M. Segal, Theodore J. Zwang, and Jacqueline K. Barton Journal of the American Chemical Society 2014 136 (17), 6470-6478
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:45109
Deposited By: Ruth Sustaita
Deposited On:22 Apr 2014 17:26
Last Modified:10 Nov 2021 17:00

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