43Ca2+ â Paramagnetic impact on DNA polymerase beta function as it relatesto a molecular pharmacology of leukemias

Human acute myeloblastleukemia HL60 cells overexpresses a beta - type DNA polymerase (EC 2.7.7.7) which 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 isotopes mentioned are 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. This43Ca – promoted enzyme hyper - suppression 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 confirms a concept 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 for molecular pharmacology of cancers is in a focus.