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Open Access DNA Polymerase Inhibition by High Kinetic Stability of T-HgII-T Base Pairs

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A fluorescent surrogate of thymidine called DMAT was used for the first fluorescence-based study of HgII binding to discrete T-T sites in duplex DNA. The fluorescent properties of DMAT-A base pairs were highly sensitive to wild-type T-HgII-T base pair formation at an adjacent site, allowing for a determination of the precise thermodynamic and kinetic parameters of these metal binding reactions. T-HgII-T complexes exhibited equilibrium dissociation constants of K d ≈ 8–50 nM. These high-affinity binding interactions are characterized by very slow association and dissociation kinetics (k on ≈ 104– 105 M–1s–1, k off ≈ 10–4 – 10–3s–1), revealing exceptionally high kinetic stabilities of T-HgII-T base pairs (half-lives = 0.3–1.3 h). Duplex DNA containing DMAT and no T-T mismatch exhibited nonspecific HgII binding affinities of K d ≈ 2.0 μM. The high kinetic stabilities of T-HgII-T resulted in the inhibition of dynamic processes such as DNA strand invasion and strand displacement during enzymatic DNA synthesis, which led to premature chain termination. These results demonstrated that T-HgII-T base pairs are kinetically distinct from T-A base pairs and therefore are likely to disrupt DNA metabolism in vivo.
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Document Type: Research Article

Affiliations: Department of Chemistry University of Zurich Winterthurerstrasse 190, CH-8057 Zurich;, Email: [email protected]

Publication date: April 1, 2017

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  • International Journal for Chemistry and Official Membership Journal of the Swiss Chemical Society (SCS) and its Divisions

    CHIMIA, a scientific journal for chemistry in the broadest sense, is published 10 times a year and covers the interests of a wide and diverse readership. Contributions from all fields of chemistry and related areas are considered for publication in the form of Review Articles and Notes. A characteristic feature of CHIMIA are the thematic issues, each devoted to an area of great current significance.

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