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The discovery that peptide nucleic acids (PNA) mimic DNA and RNA by …

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- Peptide nucleic acid–DNA duplexes: Long range hole migration from an internally linked anthraquinone

Peptide nucleic acid–DNA duplexes: Long range hole migration from an internally linked anthraquinone

Bruce Armitage, Danith Ly, Troels Koch, Henrik Frydenlund, Henrik Ørum, Hans G. Batz, and Gary B. Schuster

PNAS November 11, 1997 vol. 94 no. 23 12320-12325


The discovery that peptide nucleic acids (PNA) mimic DNA and RNA by forming complementary duplex structures following Watson–Crick base pairing rules opens fields in biochemistry, diagnostics, and medicine for exploration. Progress requires the development of modified PNA duplexes having unique and well defined properties. We find that anthraquinone groups bound to internal positions of a PNA oligomer intercalate in the PNA–DNA hybrid. Their irradiation with near-UV light leads to electron transfer and oxidative damage at remote GG doublets on the complementary DNA strand. This behavior mimics that observed in related DNA duplexes and provides the first evidence for long range electron (hole) transport in PNA–DNA hybrid. Analysis of the mechanism for electron transport supports hole hopping.


Peptide nucleic acid (PNA) oligomers are DNA/RNA analogs (see Fig. 1) in which the natural sugar–phosphate backbone is replaced by a synthetic peptide backbone (1). PNA oligomers that contain purine and pyrimidine nucleobases hybridize with complementary DNA and RNA strands to form right-handed, double-helical complexes according to the Watson–Crick rules of hydrogen bond-mediated base pair formation (2). Although much has been learned about the structural (3) and thermodynamic (4) factors involved in hybridization, little is known about the chemical reactivity of PNA/DNA hybrids. It is crucial to understand how PNA/DNA hybrids mimic the reactions and functions of duplex DNA. Of immediate importance for their application as clinical diagnostic agents is investigation of the conductivity of DNA and its PNA analogs (5, 6). 

DNA must balance the dual requirements of chemical stability and ease of transcription and replication (7). It is clear that DNA is far from inert toward a variety of different reactive species, particularly oxidizing agents. Oxidative damage to DNA produced by normal metabolism, deep-UV laser irradiation (8), gamma rays (9), or pulse radiolysis (10) accumulates at guanine residues, an effect attributed to one-dimensional migration of a radical cation (“hole”) along the DNA helix (11). Both the low oxidation potential and reactivity of the guanine radical cation contribute to the effectiveness of guanine as a trap for the migrating hole. Because guanine lesions may be the major cause of mutations (12), intense attention is focused on understanding the conductivity properties of DNA to elucidate the mechanisms by which migration of oxidative damage occurs (13). In this regard, the recent reports by Barton and coworkers are particularly important (14, 15). They describe a system consisting of a rhodium complex that is covalently linked to one end of a DNA duplex. Irradiation caused damage to the DNA more than 30 Å from where the complex was presumed to intercalate. This observation opens up exciting opportunities to study the factors that control hole migration in nucleic acids.

Photosensitizers often react with nucleic acids by single electron transfer to oxidize a base. Recent findings reveal that the light-induced reactions of a photosensitizer bound to duplex DNA by intercalation frequently generate alkali-dependent cleavage sites selectively at the 5′-G of G-purine doublets, with a strong preference for GG steps. These photosensitizers include substituted anthraquinones (16, 17), naphthalimides (18, 19), a rhodium metal complex (14), and riboflavin (20). Breslin and Schuster (17) demonstrated unambiguously that GG-selective, photoinduced damage of DNA arises by an electron transfer pathway from an intercalated anthraquinone. Time-resolved spectroscopy reveals that the excited state of the quinone accepts an electron from a base in the DNA within 20 ps of excitation (21). The base radical cation (hole) can either recombine with the electron, be trapped by reaction with water and/or oxygen, or migrate along the DNA helix to the lowest oxidation potential sites that serve as traps (22, 23).

We prepared a series of PNA oligomers with anthraquinone derivatives (AQ) covalently linked to internal positions. The ability of the quinone to photosensitize DNA damage by electron transfer when bound to the duplex by intercalation suggested it could serve a similar role in PNA-containing duplexes. The inability of common intercalators to bind to PNA (24) required that the quinone chromophore be covalently linked to the PNA backbone. The facile modification of PNA at internal residues as well as the superior hybridization properties of PNA oligomers offer distinct advantages relative to synthesis of modified DNA oligomers. Irradiation of the anthraquinone in the hybrid duplex leads to long distance hole migration and damage at GG sites in the DNA strand. Additional experiments reveal the mechanism for hole migration by its directional preference in the stacked base pairs of a PNA–DNA hybrid duplex.


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