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Nucleic Acids Research Advance Access published online on April 10, 2007
Nucleic Acids Research, doi:10.1093/nar/gkl1166
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Nuclear localization of human DNA mismatch repair protein exonuclease 1 (hEXO1)

Nina Østergaard Knudsen1, Finn Cilius Nielsen2, Lena Vinther1, Ronni Bertelsen1, Steen Holten-Andersen1, Sascha Emilie Liberti1, Robert Hofstra3, Krista Kooi3 and Lene Juel Rasmussen1,*

1Department of Science, Systems and Models, Roskilde University, Denmark, 2Department of Clinical Biochemistry, University Hospital of Copenhagen, Denmark and 3Department of Medical Genetics, University of Groningen, The Netherlands

*To whom correspondence should be addressed. Tel: +45 46742728; Fax: +45 46 74 30 11; Email: ljr{at}ruc.dk

Received September 12, 2006. Revised December 19, 2006. Accepted December 20, 2006.

Human exonuclease 1 (hEXO1) is implicated in DNA mismatch repair (MMR) and mutations in hEXO1 may be associated with hereditary nonpolyposis colorectal cancer (HNPCC). Since the subcellular localization of MMR proteins is essential for proper MMR function, we characterized possible nuclear localization signals (NLSs) in hEXO1. Using fluorescent fusion proteins, we show that the sequence 418KRPR421, which exhibit strong homology to other monopartite NLS sequences, is responsible for correct nuclear localization of hEXO1. This NLS sequence is located in a region that is also required for hEXO1 interaction with hMLH1 and we show that defective nuclear localization of hEXO1 mutant proteins could be rescued by hMLH1 or hMSH2. Both hEXO1 and hMLH1 form complexes with the nuclear import factors importin ß/{alpha}1,3,7 whereas hMSH2 specifically recognizes importin ß/{alpha}3. Taken together, we infer that hEXO1, hMLH1 and hMSH2 form complexes and are imported to the nucleus together, and that redundant NLS import signals in the proteins may safeguard nuclear import and thereby MMR activity.


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M. El-Shemerly, D. Hess, A. K. Pyakurel, S. Moselhy, and S. Ferrari
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[Abstract] [Full Text] [PDF]


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