DNA-Mediated Charge Transport in Redox Sensing and Signaling

Abstract

The transport of charge through the DNA base pair stack offers a route to carry out redox chemistry at a distance. Here we describe characteristics of this chemistry that have been elucidated and how this chemistry may be utilized within the cell. The shallow distance dependence associated with these redox reactions permits DNA-mediated signaling over long molecular distances in the genome and facilitates the activation of redox-sensitive transcription factors globally in response to oxidative stress. The long-range funneling of oxidative damage to sites of low oxidation potential in the genome also may provide a means of protection within the cell. Furthermore, the sensitivity of DNA charge transport to perturbations in base pair stacking, as may arise with base lesions and mismatches, may be used as a route to scan the genome for damage as a first step in DNA repair. Thus, the ability of double helical DNA, in mediating redox chemistry at a distance, provides a natural mechanism for redox sensing and signaling in the genome.

Subunit D of RNA Polymerase from Methanosarcina acetivorans Contains Two Oxygen-labile [4Fe-4S] Clusters

“…The additional immunoreactive proteins in the eluates are degradation products of unassembled His-D and His-D⌬D3, similar to the appearance of Rpb3 degradation products when affinitytagged Rpb3 is expressed in yeast (31-33). (34), indicating that these cofactors are a common, but not universal, feature of DNA processing enzymes. In many of these enzymes, the [4Fe-4S] cluster is important to the structural stability of the enzyme and serves to monitor the redox state of the cell and modulate enzyme activity.…”

Neil3 and NEIL1 DNA Glycosylases Remove Oxidative Damages from Quadruplex DNA and Exhibit Preferences for Lesions in the Telomeric Sequence Context

“…Because of their G-rich nature, G4-forming sequences are vulnerable targets for oxidation through DNA charge transport (32,33). For example, telomeric DNA (TTAGGG) n is more sensitive to UVA radiation (34) and hydrogen peroxide (35) than non-telomeric DNA with the same nucleotide composition.…”

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

“…Given that DNA facilitates charge transport (CT) over long molecular distances (5,6) and this CT chemistry is sensitive to the wide variety of lesions that perturb DNA base stacking (7,8), our laboratory has proposed that repair proteins exploit this unique property of DNA to search for damage (9)(10)(11). Several DNA repair proteins contain redox-active [4Fe-4S] clusters that are not required for folding (12,13).…”

“…Examples of these proteins from the BER pathway, EndoIII, and MutY, are activated toward oxidation as they bind DNA (14)(15)(16). While EndoIII effectively removes oxidized pyrimidines, the repair protein is found in very low copy number in E. coli (approximately 500 copies per cell) (17,18). Surprisingly, MutY, which removes adenine from 8-oxo-G:A mismatches, is found in even lower copy number with only approximately 30 copies per cell (19).…”