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First published on November 17, 2004; DOI: 10.1124/mol.104.004937

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Received for publication July 13, 2004.
Revised November 15, 2004.
Accepted for publication November 16, 2004.

N3-methyladenine induces early poly (ADP-ribosylation), reduction of NF-kB DNA binding ability and nuclear up-regulation of telomerase activity

Lucio Tentori 1, Olindo Forini 1, Emanuela Fossile 1, Alessia Muzi 1, Matteo Vergati 1, Ilaria Portarena 1, Carla Amici 1, Barry Gold 2, Grazia Graziani 1*

1 University of Rome 2 University of Nebraska Medical Center, Omaha, Nebraska

* Address correspondence to: E-mail: graziani{at}uniroma2.it

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 of nuclear poly(ADP-ribose) polymerase-1 (PARP-1) expression and Nuclear Factor-kB (NF-kB) activity. Moreover, DNA damage generated by N3-methyladenine induced a marked decrease of 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-kB activity thus preventing the appearance of necrosis. On the other hand, since PARP-1 is a component of the base excision repair (BER), the combination of Me-Lex + PARP-1 inhibitor triggered apoptosis due to disruption of BER process. In conclusion, the present study provides new insight in 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 co-ordinator of methylpurine repair.


Key words: NFkappaB, Apoptosis, DNA damage and repair, Mechanisms of cell killing/apoptosis, Resistance




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