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 hop ping between CG base pairs.(1-5) The injected holes oxidize remote G-sites, particularly sites comprising sequences of multiple GC base pairs.(1-22) W hen not aligned in parallel, condensed-phase DNA duplexes are electrically insulating, but when aligned their one-dimensional conductivity in the dire ction of the aligned long axes increases at least 10(3) fold The conductivi ty of 600 nm long DNA "ropes'' exceeds 10(3) Omega (-1) cm(-1,25) a value t ypical of degenerate semiconductors and only two orders of magnitude below that of conventional metals like iron. The increase is attributed to the hi gh unidirectional polarizability of DNA, which has been theoretically estim ated to be 1.5x10(-27) F m(-2), 13 orders of magnitude greater than that of water It is proposed that the cause of the high unidirectional polarizabil ity 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 bu ildup of high concentrations of oxidants like H2O2 and NO is usually avoide d in cells, their concentrations can exceed 1 nM,(27) a value translating t o > 10(9) 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 oxid ative damage: When an essential element of the genome is attacked by an oxi dizing agent, a less essential element of their genome is sacrificially oxi dized. The sacrificially oxidized domain may have only a protective functio n, or it may have an essential function the transient loss of which does no t lead to cellular damage within the characteristic period required for dam age recognition, excision and repair For cathodic protection of the essenti al parts of the genome, the sacrificially oxidized domain must be (a) in el ectronic contact with the protected domain and (b) more reducing and more r apidly oxidized than the protected domain. The redox potentials of the four bases of DNA vs. NHE at pH 7 are G, 1.04 V; T, 1.29 V; A, 1.32 V; and C, 1 .44 +/-0.02 V.(30-32) Not only is G the most reducing of bases, but its cat alytic one-electron oxidation kinetics in poly-GC sequences is particularly rapid The redox potentials of the GC and AT base pairs, estimated by avera ging the potentials of their constituent bases are, respectively, 1.24 and 1.31 V. There can be three types of sacrificially oxidized domains, differi ng in their electronic conductivity: (a) Long, highly polarizable, electron ically 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 ar e proximal to, or terminating, the protected conductive double-stranded seq uence. These are exemplified by the 12-20 base long G-rich telomeric overha ng; and (c) organized, moderately polarizable and somewhat electronically c onductive arrays of aligned G-rich single strands, exemplified by the K+-co mplexes of G-tetrads, the existence of which has been verified so far only in vitro. 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 ass isted by Michael Faraday.(34) If the hypothesis of cathodic protection of e ssential chromosomal domains is valid, then aging and genomic instability o f cells may reflect the loss of protection against oxidative damage.