TY - JOUR AU - Shatalov, Oleg A. AU - Grigoryev, Maxim E. AU - Bukhvostov, Alexander A. AU - Kuznetsov, Dmitry A. PY - 2008/12/12 Y2 - 2024/03/29 TI - A Nuclear Spin Selective Control over the DNA Repair Key Enzyme Might Renovate the Cancer–Fight Paradigm. DNA Polymerase Beta to Engage with a Magnetic Isotope Effect JF - JOURNAL OF ADVANCES IN CHEMISTRY JA - JAC VL - 4 IS - 3 SE - Articles DO - 10.24297/jac.v4i3.953 UR - https://rajpub.com/index.php/jac/article/view/953 SP - 554-562 AB - <p>DNA Polymerase Beta (EC 2.7.7.7) is found to be operated by magnetic isotope effect (MIE) of Calcium once the Mg<sup>2+</sup> ions replaced with the stable <sup>43</sup>Ca<sup>2+ </sup>isotopes inside the enzyme catalytic sites. The isotope mentioned is the only paramagnetic species of the Calcium isotopic set with a 0.135 natural abundance value and the negative 7/2 nuclear spin providing a nuclear magnetic moment equal to 1.317 Bohr magnetons. As compared to the Mg/<sup>40</sup>Ca substitution, a 2.25-fold enzyme inhibition has been shown to provethe<sup>43</sup>Ca-MIE dependent mode of the catalysis turning down.An ion-radical mechanism based on the singlet – triplet conversion of the enzyme generated intermediates (ion-radical pairs) is found to be engaged once the paramagnetic metal isotope involved into the catalysis studied.The MIE promotes a primary reaction in DNA synthesis constituting in electron transfer between the ion – radical forming partners, [Ca(H<sub>2</sub>O)<em><sub>n</sub></em><sup>2+</sup>] and [Ca<sup>2+</sup>(dNTP)]. Once the metal isotope substitution takes place inside just one of two DNA Polymerase Beta catalytic sites, a consequent<sup>43</sup>Ca – promoted inhibition leads to a residual synthesis of shorted DNA fragments that counts 25 – 35 nucleotides in length contrasting with the 180<strong><em>n</em></strong> – 210<strong><em>n</em></strong> DNA produced by either intact or<sup>40</sup>Ca – loaded polymerase. Being occurred simultaneously with a marked MIE – promoted enzyme inhibition, this fact itself makes possible to consider these short (“size-invalid”) DNA segments hardly efficient in the DNA base – excision repair. The latter is a survival factor in leukemic cells where the DNApolβ was found overexpressed. That supports a standpoint considering theDNApolβ a legitimate target for antitumor agents since its inhibition deprives the malignant cell from a DNA base – excision repair in neoplasma. A possible trend making role of these data in the current developments on a novel concept - establishing chemical background for cancer therapies is in a focus.</p> ER -