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ORIGINAL ARTICLE

N3-Methyladenine Induces Early Poly(ADP-Ribosylation), Reduction of Nuclear Factor-B DNA Binding Ability, and Nuclear Up-Regulation of Telomerase Activity

Departments of Neuroscience (L.T., O.F., E.F., A.M., M.V., I.P., G.G.) and Biology (C.A.), University of Rome "Tor Vergata", Rome, Italy; Eppley Institute for Research in Cancer and Allied Diseases and Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska (B.G.)

Abstract

Methylation of N3-adenine represents a novel pharmacological strategy for the treatment of resistant tumors. However, little is known about the biochemical pathways involved in cell death induced by N3-methyladenine. In the present study, we show that MeOSO₂ (CH₂)₂-lexitropsin (Me-Lex), a compound generating almost exclusively N3-methyladenine (>99%), provoked a burst of poly(ADP-ribosylation) and loss of mitochondrial membrane potential in leukemia cells. These events were followed by a marked decrease in nuclear poly(ADP-ribose) polymerase-1 (PARP-1) expression and nuclear factor-B (NF-B) activity. Moreover, DNA damage generated by N3-methyladenine induced a marked decrease in telomerase in the cytosol that was accompanied by a transient up-regulation of activity in the nucleus, as a consequence of nuclear translocation of telomerase in response to genotoxic damage. PARP-1 inhibition blocked ADP-ribose polymer formation, preserved mitochondrial membrane integrity, and counteracted the reduction of NF-B activity, thus preventing the appearance of necrosis. On the other hand, because PARP-1 is a component of the base excision repair (BER), the combination of Me-Lex + PARP-1 inhibitor triggered apoptosis as a result of disruption of BER process. In conclusion, the present study provides new insight into the cellular response to N3-adenine-selective methylating agents that can be exploited for the treatment of tumors unresponsive to classical wide-spectrum methylating agents. Moreover, the results underline the central and paradoxical role of PARP-1 in cell death induced by N3-methyladenine: effector of necrosis and coordinator of methylpurine repair.

Address correspondence to: Dr. Grazia Graziani, Department of Neuroscience, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy. E-mail: graziani{at}uniroma2.it

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