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Blood, 1 June 2007, Vol. 109, No. 11, pp. 5016-5026. Prepublished online as a Blood First Edition Paper on February 27, 2007; DOI 10.1182/blood-2006-08-038638. This Article Full Text (PDF) All Versions of this Article: blood-2006-08-038638v1 109/11/5016    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Oda, T. Articles by Yamashita, T. Search for Related Content PubMed PubMed Citation Articles by Oda, T. Articles by Yamashita, T. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 1, 2006 Accepted November 2, 2006 Hsp90 regulates the Fanconi anemia DNA damage response pathway Tsukasa Oda, Toshiya Hayano, Hidenobu Miyaso, Nobuhiro Takahashi, and Takayuki Yamashita* Lab of Molecular Genetics, Dept of Molecular & Cellular Bio, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan Dept of Applied Biological Science, Tokyo University of Agriculture and Technology, Tokyo, Japan Dept of Bioenvironmental Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan * Corresponding author; email: y-taka{at}showa.gunma-u.ac.jp. Heat shock protein 90 (Hsp90) regulates diverse signaling pathways. Emerging evidence suggests that Hsp90 inhibitors such as 17-allylamino-17-demethoxygeldanamycin (17-AAG) enhance DNA damage-induced cell death, suggesting that Hsp90 may regulate cellular responses to genotoxic stress. However, the underlying mechanisms are poorly understood. Here, we show that the Fanconi anemia (FA) pathway is involved in the Hsp90-mediated regulation of genotoxic stress response. In the FA pathway, assembly of eight FA proteins including FANCA into a nuclear multiprotein complex, and the complex-dependent activation of FANCD2 are critical events for cellular tolerance against DNA crosslinkers. Hsp90 associates with FANCA, in vivo and in vitro, in a 17-AAG-sensitive manner. Disruption of the FANCA/Hsp90 association by cellular treatment with 17-AAG induces rapid proteasomal degradation and cytoplasmic relocalization of FANCA, leading to impaired activation of FANCD2. Furthermore, 17-AAG promotes DNA crosslinker-induced cytotoxicity, but this effect is much less pronounced in FA pathway-defective cells. Notably, 17-AAG enhances DNA crosslinker-induced chromosome aberrations. In conclusion, our results identify FANCA as a novel client of Hsp90, suggesting that Hsp90 promotes activation of the FA pathway through regulation of intracellular turnover and trafficking of FANCA, which is critical for cellular tolerance against genotoxic stress. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Evidence for subcomplexes in the Fanconi anemia pathway Annette L. Medhurst, El Houari Laghmani, Jurgen Steltenpool, Miriam Ferrer, Chantal Fontaine, Jan de Groot, Martin A. Rooimans, Rik J. Scheper, Amom Ruhikanta Meetei, Weidong Wang, Hans Joenje, and Johan P. de Winter Blood 2006 108: 2072-2080. [Abstract] [Full Text] [PDF] This article has been cited by other articles: C. S. Tremblay, F. F. Huang, O. Habi, C. C. Huard, C. Godin, G. Levesque, and M. Carreau HES1 is a novel interactor of the Fanconi anemia core complex Blood, September 1, 2008; 112(5): 2062 - 2070. [Abstract] [Full Text] [PDF]

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