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Effective Distance for DNA-Mediated Charge Transport between Repair Proteins

Tse, Edmund C. M. and Zwang, Theodore J. and Bedoya, Sebastian and Barton, Jacqueline K. (2019) Effective Distance for DNA-Mediated Charge Transport between Repair Proteins. ACS Central Science, 5 (1). pp. 65-72. ISSN 2374-7943. PMCID PMC6346725. doi:10.1021/acscentsci.8b00566.

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The stacked aromatic base pairs within the DNA double helix facilitate charge transport down its length in the absence of lesions, mismatches, and other stacking perturbations. DNA repair proteins containing [4Fe4S] clusters can take advantage of DNA charge transport (CT) chemistry to scan the genome for mistakes more efficiently. Here we examine the effective length over which charge can be transported along DNA between these repair proteins. We define the effective CT distance as the length of DNA within which two proteins are able to influence their ensemble affinity to the DNA duplex via CT. Endonuclease III, a DNA repair glycosylase containing a [4Fe4S] cluster, was incubated with DNA duplexes of different lengths (1.5–9 kb), and atomic force microscopy was used to quantify the binding of proteins to these duplexes to determine how the relative protein affinity changes with increasing DNA length. A sharp change in binding slope is observed at 3509 base pairs, or about 1.2 μm, that supports the existence of two regimes for protein binding, one within the range for DNA CT, one outside of the range for CT; DNA CT between the redox proteins bound to DNA effectively decreases the ensemble binding affinity of oxidized and reduced proteins to DNA. Utilizing an Endonuclease III mutant Y82A, which is defective in carrying out DNA CT, shows only one regime for protein binding. Decreasing the temperature to 4 °C or including metallointercalators on the duplex, both of which should enhance base stacking and decrease DNA floppiness, leads to extending the effective length for DNA charge transport to ∼5300 bp or 1.8 μm. These results thus support DNA charge transport between repair proteins over kilobase distances. The results furthermore highlight the ability of DNA repair proteins to search the genome quickly and efficiently using DNA charge transport chemistry.

Item Type:Article
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URLURL TypeDescription Information CentralArticle
Tse, Edmund C. M.0000-0002-9313-1290
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2019 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received: August 14, 2018; Published: January 11, 2019. We gratefully recognize the NIH (GM126904) for financial support. E.C.M.T. appreciates the Croucher Foundation for a postdoctoral fellowship. T.J.Z. is an NSF fellow (DGE-1144469). S.B. acknowledges Joseph L. Koo and Helen C. Koo for a student undergraduate research fellowship. We thank Dr. Adam N. Boynton and Kelsey M. Boyle for providing metallointercalators for this study. We are also grateful to the Caltech Center for the Chemistry of Cellular Signaling for instrumentation. This research was enabled from the use of the Autoflex MALDI TOF in the Caltech CCE Multiuser Mass Spectrometry Laboratory, acquired with funds from the DOW corporation (CCEC.DOWINSTR). AFM experiments were carried out at the Molecular Materials Research Center of the Beckman Institute of the California Institute of Technology. The authors declare no competing financial interest.
Funding AgencyGrant Number
Croucher FoundationUNSPECIFIED
NSF Graduate Research FellowshipDGE-1144469
Caltech Summer Undergraduate Research Fellowship (SURF)UNSPECIFIED
Issue or Number:1
PubMed Central ID:PMC6346725
Record Number:CaltechAUTHORS:20190111-103734017
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Official Citation:Effective Distance for DNA-Mediated Charge Transport between Repair Proteins. Edmund C. M. Tse, Theodore J. Zwang, Sebastian Bedoya, and Jacqueline K. Barton. ACS Central Science 2019 5 (1), 65-72. DOI: 10.1021/acscentsci.8b00566
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:92215
Deposited By: Tony Diaz
Deposited On:12 Jan 2019 05:54
Last Modified:24 Feb 2022 17:44

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