Human Molecular Genetics Advance Access published online on March 24, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi138
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
* To whom correspondence should be addressed. The Fanconi anemia (FA) pathway plays an important role in maintaining genomic stability and defects in this pathway cause cancer susceptibility. The FA proteins have been found to function primarily in a nuclear complex, although a cytoplasmic localization and function for several FA proteins has also been reported. In this study, we investigated the possibility that FANCA, FANCC and FANCG are subjected to active export out of the nucleus. After treatment with leptomycin B, a specific inhibitor of CRM1-mediated nuclear export, the accumulation of epitope-tagged FANCA in the nucleus increased, whereas FANCC was affected to a lesser extent, and FANCG showed no response. CRM1-mediated export of FANCA was further confirmed using CRM1 cotransfection, which led to a dramatic relocalization of FANCA to the cytoplasm. Five functional leucine-rich nuclear export sequences (NESs) distributed throughout the FANCA sequence were identified and characterized using an in vivo export assay. Simultaneous inactivation of three of these NESs resulted in a discrete but reproducible increase of FANCA nuclear accumulation. However, these NES mutations did not affect the ability of FANCA to complement the mitomycin C or cisplatin sensitivity of FA-A lymphoblasts. Surprisingly, mutations in the other two NESs resulted in an almost complete relocation of the protein to cytoplasm, suggesting that these motifs overlap with domains that are crucial for nuclear import. Taken together, these findings indicate that FANCA can be actively exported out of the nucleus by CRM1, revealing a new mechanism to regulate the function of the FA protein complex.
Received January 13, 2005
Revised March 7, 2005
Accepted March 21, 2005
Article
Identification of multiple nuclear export sequences in Fanconi anemia group A protein that contribute to CRM1-dependent nuclear export
2 Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
Frank A.E. Kruyt, E-mail: kruyt{at}vumc.nl
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Oda, T. Hayano, H. Miyaso, N. Takahashi, and T. Yamashita Hsp90 regulates the Fanconi anemia DNA damage response pathway Blood, June 1, 2007; 109(11): 5016 - 5026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E.J. Bedard, J. D. Purnell, and S. M. Ware Nuclear import and export signals are essential for proper cellular trafficking and function of ZIC3 Hum. Mol. Genet., January 15, 2007; 16(2): 187 - 198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Larder, D. Karali, N. Nelson, and P. Brown Fanconi Anemia a Is a Nucleocytoplasmic Shuttling Molecule Required for Gonadotropin-Releasing Hormone (GnRH) Transduction of the GnRH Receptor Endocrinology, December 1, 2006; 147(12): 5676 - 5689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Taniguchi and A. D. D'Andrea Molecular pathogenesis of Fanconi anemia: recent progress Blood, June 1, 2006; 107(11): 4223 - 4233. [Abstract] [Full Text] [PDF]
|
|