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DNA charge transport as a first step in coordinating the detection of lesions by repair proteins

Sontz, Pamela A. and Mui, Timothy P. and Fuss, Jill O. and Tainer, John A. and Barton, Jacqueline K. (2012) DNA charge transport as a first step in coordinating the detection of lesions by repair proteins. Proceedings of the National Academy of Sciences of the United States of America, 109 (6). pp. 1856-1861. ISSN 0027-8424. PMCID PMC3277573. doi:10.1073/pnas.1120063109.

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Damaged bases in DNA are known to lead to errors in replication and transcription, compromising the integrity of the genome. We have proposed a model where repair proteins containing redox-active [4Fe-4S] clusters utilize DNA charge transport (CT) as a first step in finding lesions. In this model, the population of sites to search is reduced by a localization of protein in the vicinity of lesions. Here, we examine this model using single-molecule atomic force microscopy (AFM). XPD, a 5′-3′ helicase involved in nucleotide excision repair, contains a [4Fe-4S] cluster and exhibits a DNA-bound redox potential that is physiologically relevant. In AFM studies, we observe the redistribution of XPD onto kilobase DNA strands containing a single base mismatch, which is not a specific substrate for XPD but, like a lesion, inhibits CT. We further provide evidence for DNA-mediated signaling between XPD and Endonuclease III (EndoIII), a base excision repair glycosylase that also contains a [4Fe-4S] cluster. When XPD and EndoIII are mixed together, they coordinate in relocalizing onto the mismatched strand. However, when a CT-deficient mutant of either repair protein is combined with the CT-proficient repair partner, no relocalization occurs. These data not only indicate a general link between the ability of a repair protein to carry out DNA CT and its ability to redistribute onto DNA strands near lesions but also provide evidence for coordinated DNA CT between different repair proteins in their search for damage in the genome.

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URLURL TypeDescription DOIArticle CentralArticle Information
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2012 by the National Academy of Sciences. Contributed by Jacqueline K. Barton, December 13, 2011 (sent for review November 1, 2011). Published online before print January 23, 2012. We thank Alison Parisian for technical assistance and Eric Olmon for preparation and purification of WT and Y82A EndoIII protein. We are also grateful to the Beckman Institute MMRC for AFM instrumentation. We also thank the National Institutes of Health (NIH) (GM49216 to J.K.B.; CA112093 to J.A.T.), and the Department of Energy (DOE) (ENIGMA program under Contract No. DE-AC02-05CH11231 to J.A.T.) for funding. We also thank the National Science Foundation (NSF) for a graduate fellowship to T.P.M. Author contributions: P.A.S., T.P.M., and J.K.B. designed research; P.A.S. and T.P.M. performed research; J.O.F. and J.A.T. contributed new reagents/analytic tools; P.A.S., T.P.M., J.O.F., J.A.T., and J.K.B. analyzed data; and P.A.S., T.P.M., J.O.F., J.A.T., and J.K.B. wrote the paper. The authors declare no conflict of interest. This article contains supporting information online at
Funding AgencyGrant Number
Department of Energy (DOE)DE-AC02-05CH11231
NSF Graduate Research FellowshipUNSPECIFIED
Subject Keywords:DNA electron transfer; iron-sulfur clusters; oxidative damage
Issue or Number:6
PubMed Central ID:PMC3277573
Record Number:CaltechAUTHORS:20120228-100512207
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Official Citation:Pamela A. Sontz, Timothy P. Mui, Jill O. Fuss, John A. Tainer, and Jacqueline K. Barton DNA charge transport as a first step in coordinating the detection of lesions by repair proteins PNAS 2012 109 (6) 1856-1861; published ahead of print January 23, 2012, doi:10.1073/pnas.1120063109
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:29503
Deposited By: Tony Diaz
Deposited On:28 Feb 2012 23:30
Last Modified:09 Nov 2021 17:07

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