Hsp90 regulates the Fanconi anemia DNA damage response pathway
Hsp90 regulates the Fanconi anemia DNA damage response pathway
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DOI：
10.1182/blood-2006-08-038638
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发表时间：
2007-06-01
期刊：
影响因子：
20.3
通讯作者：
Yamashita, Takayuki
中科院分区：
文献类型：
--
作者：
Oda, Tsukasa;Hayano, Toshiya;Yamashita, Takayuki
热休克蛋白90 （Hsp90）调控多种信号通路。新出现的证据表明，Hsp90抑制剂，如17-烯丙基氨基-17-去甲氧基格尔达霉素（17-AAG），可增强DNA损伤诱导的细胞死亡，表明Hsp90可能调节细胞对基因毒性应激的反应。然而，人们对其潜在机制知之甚少。本研究表明，Fanconi贫血（FA）通路参与了hsp90介导的基因毒性应激反应调控。在FA通路中，包括FANCA在内的8种FA蛋白组装成核多蛋白复合物，以及FANCD2的复合物依赖性激活是细胞对DNA交联剂耐受的关键事件。在体内和体外，Hsp90以17- aag敏感的方式与FANCA结合。17-AAG对FANCA/Hsp90的破坏诱导了FANCA的快速蛋白酶体降解和细胞质重定位，导致FANCD2的激活受损。此外，17-AAG促进DNA交联剂诱导的细胞毒性，但这种作用在FA通路缺陷的细胞中不太明显。值得注意的是，17-AAG增强了DNA交联剂诱导的染色体畸变。总之，我们的研究结果确定FANCA是Hsp90的新客户，表明Hsp90通过调节细胞内的周转和FANCA的运输来促进FA通路的激活，这对于细胞对遗传毒性应激的耐受至关重要。
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-medlated regulation of genotoxic stress response. In the FA pathway, assembly of 8 FA proteins including FANCA into a nuclear multiprotein complex, and the complex-dependent activation of FANCD2 are critical events for cellular tolerance against DNA cross-linkers. 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 cross-linker-Induced cytotoxicity, but this effect is much less pronounced in FA pathway-defective cells. Notably, 17-AAG enhances DNA cross-linker-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.