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J. Biol. Chem., Vol. 280, Issue 7, 6005-6015, February 18, 2005

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Interaction of DNA Fragmentation Factor (DFF) with DNA Reveals an Unprecedented Mechanism for Nuclease Inhibition and Suggests That DFF Can Be Activated in a DNA-bound State^*

Christian Korn, Sebastian R. Scholz¶, Oleg Gimadutdinow||**, Rudi Lurz, Alfred Pingoud, and Gregor Meiss

From the Institute of Biochemistry, Justus-Liebig-University Giessen, 35392 Giessen, Germany, the ^||Institute of Genetics, Kazan State University, Remlevskaja 18-28, Kazan, Russia, and the Max-Planck Institute for Molecular Genetics, Ihnestrasse 73, D-14195 Berlin-Dahlem, Germany

DNA fragmentation factor (DFF) is a complex of the DNase DFF40 (CAD) and its chaperone/inhibitor DFF45 (ICAD-L) that can be activated during apoptosis to induce DNA fragmentation. Here, we demonstrate that DFF directly binds to DNA in vitro without promoting DNA cleavage. DNA binding by DFF is mediated by the nuclease subunit, which can also form stable DNA complexes after release from DFF. Recombinant and reconstituted DFF is catalytically inactive yet proficient in DNA binding, demonstrating that the nuclease subunit in DFF is inhibited in DNA cleavage but not in DNA binding, revealing an unprecedented mode of nuclease inhibition. Activation of DFF in the presence of naked DNA or isolated nuclei stimulates DNA degradation by released DFF40 (CAD). In transfected HeLa cells transiently expressed DFF associates with chromatin, suggesting that DFF could be activated during apoptosis in a DNA-bound state.

Received for publication, November 18, 2004

^* This work was supported by Grant Pi 122/16-3 from the Deutsche Forschungsgemeinschaft. 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.

Both authors contributed equally to this work.

^¶ Member of the Graduiertenkolleg Biochemie von Nukleoproteinkomplexen.

^** Supported by the Deutscher Akademischer Austausch Dienst.

To whom correspondence should be addressed: Institute of Biochemistry, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 58, D-35392 Giessen, Germany. Tel.: 49-641-99-35404; Fax: 49-641-99-35409; E-mail: gf45{at}uni-giessen.de.

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