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J. Biol. Chem., Vol. 282, Issue 49, 35821-35830, December 7, 2007

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Sequence Elements in Both Subunits of the DNA Fragmentation Factor Are Essential for Its Nuclear Transport^*

From the Institut für Biochemie und Molekulare Zellbiologie, Abteilung Molekularbiologie, Universität Göttingen, Humboldtallee 23, Göttingen 37073, Germany

DNA cleavage is a biochemical hallmark of apoptosis. In humans, apoptotic DNA cleavage is executed by DNA fragmentation factor (DFF) 40. In proliferating cells DFF40 is expressed in the presence of its chaperone and inhibitor DFF45, which results in the formation of the DFF complex. Here, we present a systematic analysis of the nuclear import of the DFF complex. Our in vitro experiments demonstrate that the importin /β-heterodimer mediates the translocation of the DFF complex from the cytoplasm to the nucleus. Both DFF subunits interact directly with the importin /β-heterodimer. However, importin /β binds more tightly to the DFF complex compared with the individual subunits. Additionally, the isolated C-terminal regions of both DFF subunits together bind importin /β more strongly than the individual C termini. Our results from in vivo studies reveal that the C-terminal regions of both DFF subunits harbor nuclear localization signals. Furthermore, nuclear import of the DFF complex requires the C-terminal regions of both subunits. In more detail, one basic cluster in the C-terminal region of each subunit, DFF40 (RLKRK) and DFF45 (KRAR), is essential for nuclear accumulation of the DFF complex. Based on these findings two alternative models for the interaction of importin /β with the DFF complex are presented.

Received for publication, April 12, 2007 , and in revised form, October 15, 2007.

^* This work was supported by the Deutsche Forschungsgemeinschaft (Graduiertenkolleg 521: Protein-Protein-Interaktionen beim intrazellulären Transport von Makromolekülen, Do 143/19). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text and Figs. S1–S5.

¹ To whom correspondence should be addressed. Tel.: 49-551-395-972; Fax: 49-551-395-960; E-mail: ddoenec{at}gwdg.de.

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