Spiers Memorial Lecture: On the hypothesis of cathodic protection of genes

Holes (electron vacancies) injected by oxidants are transferred across <50 base pair (bp) long dissolved DNA duplexes in homogeneous solutions by hopping between CG base pairs. The injected holes oxidize remote G-sites, particularly sites comprising sequences of multiple GC base pairs. When not aligned in parallel, condensed-phase DNA duplexes are electrically insulating, but when aligned their one-dimensional conductivity in the direction of the aligned long axes increases at least 103 fold. The conductivity of 600 nm long DNA "ropes" exceeds 103 Ω−1 cm−1, a value typical of degenerate semiconductors and only two orders of magnitude below that of conventional metals like iron. The increase is attributed to the high unidirectional polarizability of DNA, which has been theoretically estimated to be 1.5 × 10−27 F m−2, 13 orders of magnitude greater than that of water. It is proposed that the cause of the high unidirectional polarizability is the rapid and concerted shift of protons between primary amines of G-, C- and A-bases of neighboring pairs of the DNA stack. Even though the buildup of high concentrations of oxidants like H2O2 and NO is usually avoided in cells, their concentrations can exceed 1 nM, a value translating to >109 oxidant-molecules per copy of the genome. Thus, oxidative attack of a cell's genome, which can be several centimeters long, is not unlikely. Some species may have evolved so that their essential chromosomal domains, including their transcribed genes, are cathodically protected against oxidative damage: When an essential element of the genome is attacked by an oxidizing agent, a less essential element of their genome is sacrificially oxidized. The sacrificially oxidized domain may have only a protective function, or it may have an essential function the transient loss of which does not lead to cellular damage within the characteristic period required for damage recognition, excision and repair. For cathodic protection of the essential parts of the genome, the sacrificially oxidized domain must be (a) in electronic contact with the protected domain and (b) more reducing and more rapidly oxidized than the protected domain. The redox potentials of the four bases of DNA s. NHE at pH 7 are G, 1.04 V; T, 1.29 V; A, 1.32 V; and C, 1.44 ± 0.02 V. Not only is G the most reducing of bases, but its catalytic one-electron oxidation kinetics in poly-GC sequences is particularly rapid. The redox potentials of the GC and AT base pairs, estimated by averaging the potentials of their constituent bases are, respectively, 1.24 and 1.31 V. There can be three types of sacrificially oxidized domains, differing in their electronic conductivity: (a) Long, highly polarizable, electronically conducting GC-rich sequences within the chromosomes, exemplified by the 1–2 kilobase (kb) long double-stranded CpG islands found at the 5′-end of genes in chromosomes of animals; (b) very short, single-stranded G-rich sequences, that are neither particularly polarizable nor conductive, but are proximal to, or terminating, the protected conductive double-stranded sequence. These are exemplified by the 12–20 base long G-rich telomeric overhang; and (c) organized, moderately polarizable and somewhat electronically conductive arrays of aligned G-rich single strands, exemplified by the K+-complexes of G-tetrads, the existence of which has been verified so far only in itro. In all three cases the protective process resembles that of steel by zinc, where the more reducing zinc is sacrificially oxidized while protecting the steel against corrosion, a process described by Humphrey Davy, who was assisted by Michael Faraday. If the hypothesis of cathodic protection of essential chromosomal domains is valid, then aging and genomic instability of cells may reflect the loss of protection against oxidative damage.