A Nuclear Spin Selective Control over the DNA Repair Key Enzyme Might Renovate the Cancerâ€“Fight Paradigm. DNA Polymerase Beta to Engage with a Magnetic Isotope Effect
Keywords:magnetic isotope effect, nuclear spin selectivity, DNArepair, 40Ca and 43Ca isotopes, ion-radical path in the metal â€“ dependent enzymatic catalysis
DNA Polymerase Beta (EC 184.108.40.206) 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 â€“ 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 â€“ 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 â€“ promoted inhibition leads to a residual synthesis of shorted DNA fragments that counts 25 â€“ 35 nucleotides in length contrasting with the 180n â€“ 210n DNA produced by either intact or40Ca â€“ loaded polymerase. Being occurred simultaneously with a marked MIE â€“ promoted enzyme inhibition, this fact itself makes possible to consider these short (â€œsize-invalidâ€) DNA segments hardly efficient in the DNA base â€“ excision repair. The latter is a survival factor in leukemic cells where the DNApolÎ² was found overexpressed. That supports a standpoint considering theDNApolÎ² a legitimate target for antitumor agents since its inhibition deprives the malignant cell from a DNA base â€“ 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.
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