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Molecular and Cellular Biology, February 2009, p. 1000-1006, Vol. 29, No. 4
0270-7306/09/$08.00+0     doi:10.1128/MCB.01131-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Nuclear Export of NBN Is Required for Normal Cellular Responses to Radiation{triangledown}

Christine S. Vissinga,1 Tiong C. Yeo,1,2 Sarah Warren,2 James V. Brawley,1,2 Jennifer Phillips,3 Karen Cerosaletti,1 and Patrick Concannon3*

Molecular Genetics Program, Benaroya Research Institute, Seattle, Washington 98101-2795,1 Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98195,2 Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908-07333

Received 17 July 2008/ Returned for modification 27 August 2008/ Accepted 3 December 2008

Nijmegen breakage syndrome arises from hypomorphic mutations in the NBN gene encoding nibrin, a component of the MRE11/RAD50/nibrin (MRN) complex. In mammalian cells, the MRN complex localizes to the nucleus, where it plays multiple roles in the cellular response to DNA double-strand breaks. In the current study, sequences in mouse nibrin required to direct the nuclear localization of the MRN complex were identified by site-specific mutagenesis. Unexpectedly, nibrin was found to contain both nuclear localizing signal (NLS) sequences and a nuclear export signal (NES) sequence whose functions were confirmed by mutagenesis. Both nuclear import and export sequences were active in vivo. Disruption of either the NLS or NES sequences of nibrin significantly altered the cellular distribution of nibrin and Mre11 and impaired survival after exposure to ionizing radiation. Mutation of the NES sequence in nibrin slowed the turnover of phosphorylated nibrin after irradiation, indicating that nuclear export of nibrin may function, in part, to downregulate posttranslationally modified MRN complex components after DNA damage responses are complete.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Genetics, University of Virginia, P.O. Box 800733, Charlottesville, VA 22908-0733. Phone: (434) 982-3288. Fax: (434) 982-1815. E-mail: patcon{at}virginia.edu

{triangledown} Published ahead of print on 15 December 2008.

Molecular and Cellular Biology, February 2009, p. 1000-1006, Vol. 29, No. 4
0270-7306/09/$08.00+0     doi:10.1128/MCB.01131-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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