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J. Biol. Chem., Vol. 281, Issue 45, 34394-34405, November 10, 2006

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MNNG-induced Cell Death Is Controlled by Interactions between PARP-1, Poly(ADP-ribose) Glycohydrolase, and XRCC1^*

From the Institut für Biochemie, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Federal Republic of Germany

PARP-1 (poly(ADP-ribose) polymerases) modifies proteins with poly(ADP-ribose), which is an important signal for genomic stability. ADP-ribose polymers also mediate cell death and are degraded by poly(ADP-ribose) glycohydrolase (PARG). Here we show that the catalytic domain of PARG interacts with the automodification domain of PARP-1. Furthermore, PARG can directly down-regulate PARP-1 activity. PARG also interacts with XRCC1, a DNA repair factor that is recruited by DNA damage-activated PARP-1. We investigated the role of XRCC1 in cell death after treatment with supralethal doses of the alkylating agent MNNG. Only in XRCC1-proficient cells MNNG induced a considerable accumulation of poly(ADP-ribose). Similarly, extracts of XRCC1-deficient cells produced large ADP-ribose polymers if supplemented with XRCC1. Consequently, MNNG triggered in XRCC1-proficient cells the translocation of the apoptosis inducing factor from mitochondria to the nucleus followed by caspase-independent cell death. In XRCC1-deficient cells, the same MNNG treatment caused non-apoptotic cell death without accumulation of poly(ADP-ribose). Thus, XRCC1 seems to be involved in regulating a poly(ADP-ribose)-mediated apoptotic cell death.

Received for publication, July 7, 2006 , and in revised form, August 25, 2006.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant ZI 541/3. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 49-3083852194; Fax: 49-3083857194; E-mail: lity{at}chemie.fu-berlin.de.

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