Nucleic Acids Research Advance Access originally published online on April 1, 2007
Nucleic Acids Research 2007 35(8):2522-2532; doi:10.1093/nar/gkl1163
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Nucleic Acids Research, 2007, Vol. 35, No. 8 2522-2532
© 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 |
Nitric oxide controls nuclear export of APE1/Ref-1 through S-nitrosation of Cysteines 93 and 310
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, and Graduate School of the Chinese Academy of Sciences, Beijing, China
*To whom correspondence should be addressed. Tel: 86 10 64888406; Email: changchen{at}moon.ibp.ac.cn
Received November 15, 2006. Revised December 20, 2006. Accepted December 20, 2006.
Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/Ref-1, abbreviated as APE1) is a molecule with dual functions in DNA repair and redox regulation of transcription factors. Accumulated work has shown that the biological activities of APE1 are sensitive to oxidative stress; however, whether APE1 functions can be regulated by nitrosative stress remains unknown. In this investigation, we found that S-nitrosoglutathion (GSNO), a nitric oxide donor and also an S-nitrosating agent, effectively stimulated nuclear export of APE1 in a CRM1-independent manner. This nuclear-cytoplasmic translocation was dependent on S-nitrosation modification of APE1, as simultaneous mutation of S-nitrosation target sites Cys93 and Cys310 completely abrogated the cytoplasmic redistribution. The translocation process was reversal and specific, as it could be reversed by reductive reagents, but could not be mimicked by H2O2. In structure, the region aa.64–80 and the beta-strand aa.311–316 in proximity to Cys93 and Cys310 were important for GSNO-induced APE1 relocalization. In addition, a defect of importin-mediated nuclear import pathway was found in the NO-insulted cells, and p50 and HDAC2 were identified as APE1 nuclear export inhibitory proteins. Together, this study may provide a novel molecular mechanism, which links nitrosative stress to APE1-associated physiological and pathological processes.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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