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J. Biol. Chem., Vol. 280, Issue 47, 39594-39600, November 25, 2005

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Importin KPNA2 Is Required for Proper Nuclear Localization and Multiple Functions of NBS1^*

Shun-Fu Tseng1, Chun-Yu Chang1, Kou-Juey Wu, and Shu-Chun Teng¶2

From the Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei 10018, Taiwan, the Institute of Biochemistry, National Yang-Ming University, Taipei, Taiwan, and the ^¶Institute of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

Nijmegen breakage syndrome (NBS) is a chromosomal-instability syndrome associated with cancer predisposition, radiosensitivity, microcephaly, and growth retardation. The NBS gene product, NBS1, is a component of the MRE11-RAD50-NBS1 (MRN) complex, a central player associated with double strand break (DSB) repair. In response to radiation, NBS1 is phosphorylated by ATM, and the MRN complex relocalizes to form punctate nuclear foci for DNA repair. NBS1 controls both the nuclear localization of the MRN complexes and radiation-induced focus formation. We report here that the KPNA2 (importin 1) is important for the normal nuclear localization of the MRN complex and its proper formation of the nuclear foci. KPNA2 is the only member of the importin family that physically interacts with NBS1, and the KPNA2-mediated nucleus localization sequence (NLS) is mapped to amino acid residues 461-467 of NBS1 that is sufficient for both the interaction with KPNA2 and the proper nuclear localization. Inhibition of KPNA2 or blockage of the KPNA2 interaction with NBS1 results in a reduction of radiation-induced nuclear focus accumulation, DSB repair, and cell cycle checkpoint signaling of NBS1. Collectively, our results strongly suggest that an interaction with KPNA2 contributes to nuclear localization and multiple tumor suppression functions of the NBS1 complex.

Received for publication, August 1, 2005 , and in revised form, September 23, 2005.

^* This work was supported in part by the National Health Research Institutes (Grant NHRI-EX94-9329SI to K.-J. W. and Grant NHRI-EX94-9328SI to S.-C. T), by the National Research Program for Genomic Medicine, Department of Health (Grant DOH94-TDG-111-012 to K.-J. W.), and by the National Science Council (Grant NSC-93-2320-B-002-38 to S.-C. T. and Grant NSC-93-2320-B-010-062 to K.-J. W.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 886-2-2312-3456 (ext. 8282); Fax: 886-2-23915293; E-mail: scteng{at}ha.mc.ntu.edu.tw.

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