The long term objective of this proposed application is an understanding of DNA-mediated charge transport (CT) chemistry and biology and implications with respect to oxidative DNA damage and repair. Studies in our laboratory have shown that DNA CT can proceed over long molecular distances to effect damage, in a sequence- and structure-dependent fashion, and can be modulated by DNA-binding proteins. The reaction is exquisitely sensitive to stacking. It is proposed now to delineate the biological consequences and opportunities for DNA CT. Oxidative damage to DNA within the cell nucleus will be explored using intercalating photooxidants. DNA damage will be probed in telomeric regions of the chromosome and within CpG islands bordering exons to test whether these regions provide sinks to which damage is funneled by DNA CT. Transcriptionally active versus inactive regions will be compared. The distance range for CT damage will be established in vivo by triplex targeting. Whether DNA-binding proteins utilize DNA CT advantageously will also be examined. The family of base excision repair enzymes, notably MutY and Endo III, will be probed as to their DNA-bound redox chemistry. Transient absorption, EPR, electrochemistry, on DNA-modified electrodes and biochemical methods will be utilized to characterize protein/DNA CT using wild type and mutant proteins. Spin traps to probe DNA-mediated CT involving the DNA-bound protein will be developed. Also the transcriptional activator, SoxR will be examined to test whether DNA-mediated CT is exploited for long range signaling and activation. Oxidation of the DNA-bound transcription factor at long range in a DNA-mediated reaction will be examined using electrochemistry and transient absorption spectroscopy and the long range activation of SoxR will be probed biochemically. In parallel, transient absorption, fluorescence and biochemical methods will be utilized in well-defined oligonucleotide assemblies to probe the important characteristics of DNA CT relevant to the biological context. Modified bases and guanines will serve as targets of oxidation. Electron versus hole transport will be examined and compared. Other chemical traps for reductive and oxidative CT besides guanine damage will be enlisted including thymine dimer repair. ? ?
| Grodick, Michael A; Segal, Helen M; Zwang, Theodore J et al. (2014) DNA-mediated signaling by proteins with 4Fe-4S clusters is necessary for genomic integrity. J Am Chem Soc 136:6470-8 |
| Arnold, Anna R; Barton, Jacqueline K (2013) DNA protection by the bacterial ferritin Dps via DNA charge transport. J Am Chem Soc 135:15726-9 |
| Pheeney, Catrina G; Arnold, Anna R; Grodick, Michael A et al. (2013) Multiplexed electrochemistry of DNA-bound metalloproteins. J Am Chem Soc 135:11869-78 |
| Muren, Natalie B; Olmon, Eric D; Barton, Jacqueline K (2012) Solution, surface, and single molecule platforms for the study of DNA-mediated charge transport. Phys Chem Chem Phys 14:13754-71 |
| Sontz, Pamela A; Muren, Natalie B; Barton, Jacqueline K (2012) DNA charge transport for sensing and signaling. Acc Chem Res 45:1792-800 |
| Sontz, Pamela A; Mui, Timothy P; Fuss, Jill O et al. (2012) DNA charge transport as a first step in coordinating the detection of lesions by repair proteins. Proc Natl Acad Sci U S A 109:1856-61 |
| Genereux, Joseph C; Wuerth, Stephanie M; Barton, Jacqueline K (2011) Single-step charge transport through DNA over long distances. J Am Chem Soc 133:3863-8 |
| Olmon, Eric D; Hill, Michael G; Barton, Jacqueline K (2011) Using metal complex reduced states to monitor the oxidation of DNA. Inorg Chem 50:12034-44 |
| Romano, Christine A; Sontz, Pamela A; Barton, Jacqueline K (2011) Mutants of the base excision repair glycosylase, endonuclease III: DNA charge transport as a first step in lesion detection. Biochemistry 50:6133-45 |
| Mui, Timothy P; Fuss, Jill O; Ishida, Justin P et al. (2011) ATP-stimulated, DNA-mediated redox signaling by XPD, a DNA repair and transcription helicase. J Am Chem Soc 133:16378-81 |
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