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DNA Charge Transport for Sensing and Signaling

Sontz, Pamela A. and Muren, Natalie B. and Barton, Jacqueline K. (2012) DNA Charge Transport for Sensing and Signaling. Accounts of Chemical Research, 45 (10). pp. 1792-1800. ISSN 0001-4842. PMCID PMC3495616. doi:10.1021/ar3001298. https://resolver.caltech.edu/CaltechAUTHORS:20121116-100524704

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Abstract

The DNA duplex is an exquisite macromolecular array that stores genetic information to encode proteins and regulate pathways. Its unique structure also imparts chemical function that allows it also to mediate charge transport (CT). We have utilized diverse platforms to probe DNA CT, using spectroscopic, electrochemical, and even genetic methods. These studies have established powerful features of DNA CT chemistry. DNA CT can occur over long molecular distances as long as the bases are well stacked. The perturbations in base stacking that arise with single base mismatches, DNA lesions, and the binding of some proteins that kink the DNA all inhibit DNA CT. Significantly, single molecule studies of DNA CT show that ground state CT can occur over 34 nm if the duplex is well stacked; one single base mismatch inhibits CT. The DNA duplex is an effective sensor for the integrity of the base pair stack. Moreover, the efficiency of DNA CT is what one would expect for a stack of graphite sheets: equivalent to the stack of DNA base pairs and independent of the sugar-phosphate backbone. Since DNA CT offers a means to carry out redox chemistry from a distance, we have considered how this chemistry might be used for long range biological signaling. We have taken advantage of our chemical probes and platforms to characterize DNA CT in the context of the cell. CT can occur over long distances, perhaps funneling damage to particular sites and insulating others from oxidative stress. Significantly, transcription factors that activate the genome to respond to oxidative stress can also be activated from a distance through DNA CT. Numerous proteins maintain the integrity of the genome and an increasing number of them contain [4Fe-4S] clusters that do not appear to carry out either structural or enzymatic roles. Using electrochemical methods, we find that DNA binding shifts the redox potentials of the clusters, activating them towards oxidation at physiological potentials. We have proposed a model that describes how repair proteins may utilize DNA CT to efficiently search the genome for lesions. Importantly, many of these proteins occur in low copy numbers within the cell, and thus a processive mechanism does not provide a sufficient explanation of how they find and repair lesions before the cell divides. Using atomic force microscopy and genetic assays, we show that repair proteins proficient at DNA CT can relocalize in the vicinity of DNA lesions and can cooperate in finding lesions within the cell. Conversely, proteins defective in DNA CT cannot relocalize in the vicinity of lesions and do not assist other proteins involved in repair within the cell. Moreover such genetic defects are associated with disease in human protein analogues. As we continue to unravel this chemistry and discover more proteins with redox cofactors involved in genome maintenance, we are learning more regarding opportunities for long range signaling and sensing, and more examples of DNA CT chemistry that may provide critical functions within the cell.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/ar3001298DOIArticle
http://pubs.acs.org/doi/abs/10.1021/ar3001298PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495616/PubMed CentralArticle
ORCID:
AuthorORCID
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2012 American Chemical Society. Published In Issue October 16, 2012; Article ASAP August 03, 2012; Received: May 03, 2012. We are grateful to the NIH for their financial support. We thank Dr. Eric D. Olmon for his help designing and constructing figures. We thank also ourmany co-workers involved in these experiments who had the courage and imagination to explore this chemistry.
Funders:
Funding AgencyGrant Number
NIHUNSPECIFIED
Issue or Number:10
PubMed Central ID:PMC3495616
DOI:10.1021/ar3001298
Record Number:CaltechAUTHORS:20121116-100524704
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20121116-100524704
Official Citation:DNA Charge Transport for Sensing and Signaling Pamela A. Sontz, Natalie B. Muren, and Jacqueline K. Barton Accounts of Chemical Research 2012 45 (10), 1792-1800
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:35508
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:16 Nov 2012 21:28
Last Modified:09 Nov 2021 23:15

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