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

Abstract

DNA Polymerase Beta (EC 2.7.7.7) is found to be operated by magnetic isotope effect (MIE) of Calcium once the Mg²⁺ ions replaced with the stable ⁴³Ca²⁺ 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/⁴⁰Ca substitution, a 2.25-fold enzyme inhibition has been shown to provethe⁴³Ca-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(H₂O)_n²⁺] and [Ca²⁺(dNTP)]. Once the metal isotope substitution takes place inside just one of two DNA Polymerase Beta catalytic sites, a consequent⁴³Ca – promoted inhibition leads to a residual synthesis of shorted DNA fragments that counts 25 – 35 nucleotides in length contrasting with the 180n – 210n DNA produced by either intact or⁴⁰Ca – loaded polymerase. Being occurred simultaneously with a marked MIE – promoted enzyme inhibition, this fact itself makes possible to consider these short (“size-invalidâ€) 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.