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-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.

Magnetic field and nuclear spin influence on the DNA synthesis rate

“…Moreover, the rates of the reaction were equal in presence of ions having different masses and equal spin, which excluded the classical isotope effect manifestation. The magnetic isotope effect was also revealed in the reaction of DNA synthesis 14 . Complete substitution of the natural magnesium ions pool ( Mg: Mg: Mg 8:1:1) with the paramagnetic ones decreased the DNAPol catalytic activity 14 .…”

“…The magnetic isotope effect was also revealed in the reaction of DNA synthesis 14 . Complete substitution of the natural magnesium ions pool ( Mg: Mg: Mg 8:1:1) with the paramagnetic ones decreased the DNAPol catalytic activity 14 . The effect was strong enough to provide for a pronounced anti-proliferation effect on HL-60 human acute myeloid leukemia cells 15 , 16 .…”

“…Lomonosov Moscow State University, faculty of Physics, Lenin Hills 1/2, Moscow, Russia 119192. * email: dvzlenko@gmail.com ∼ 8:1:1) with the paramagnetic ones decreased the DNAPolβ catalytic activity 14 . The effect was strong enough to provide for a pronounced anti-proliferation effect on HL-60 human acute myeloid leukemia cells 15,16 .…”

Magnetic Field and Nuclear Spin Influence on the DNA Synthesis Rate

“…Moreover, the rates of the reaction were equal in presence of ions having different masses and equal spin, which excluded the classical isotope effect influence. The magnetic isotope effect was also revealed in the reaction of DNA synthesis 9 . Complete substitution of the natural magnesium ions pool ( 24 Mg: 25 Mg: 26 Mg ∼ 8:1:1) with the paramagnetic ones decreases the DNAPolβ catalytic activity 9 .…”

“…The magnetic isotope effect was also revealed in the reaction of DNA synthesis 9 . Complete substitution of the natural magnesium ions pool ( 24 Mg: 25 Mg: 26 Mg ∼ 8:1:1) with the paramagnetic ones decreases the DNAPolβ catalytic activity 9 . The effect was strong enough to provide for a pronounced anti-proliferation effect on HL-60 human acute myeloid leukemia cells 10,11 .…”