Interaction of the fanconi anemia proteins and BRCA1 in a common pathway
Interaction of the fanconi anemia proteins and BRCA1 in a common pathway
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DOI：
10.1016/s1097-2765(01)00173-3
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发表时间：
2001-02-01
期刊：
影响因子：
16
通讯作者：
D'Andrea, AD
中科院分区：
文献类型：
--
作者：
Garcia-Higuera, I;Taniguchi, T;D'Andrea, AD
范可尼贫血（FA）是一种常染色体隐性遗传性癌症易感性疾病，其特征是细胞对丝裂霉素C和电离辐射敏感。虽然已经克隆了六个FA基因（A，C，D2，E，F和G亚型），但它们与DNA修复的关系仍然未知。在目前的研究中，我们表明，一个核复合物含有FANCA，FANCC，FANCF，和FANCG蛋白是必需的FANCD 2蛋白的激活monoubiquitinated亚型。在正常（非FA）细胞中，FANCD 2响应于DNA损伤而被单泛素化，并靶向核灶（点）。激活的FANCD 2蛋白与乳腺癌易感蛋白BRCA 1共定位于电离辐射诱导的病灶和减数分裂染色体的联会复合体中。因此，FANCD 2蛋白提供了FA蛋白复合物和细胞BRCA 1修复机制之间缺失的环节。该途径的破坏导致所有FA亚型共有的细胞和临床表型。
Fanconi anemia (FA) is a human autosomal recessive cancer susceptibility disorder characterized by cellular sensitivity to mitomycin C and ionizing radiation. Although six FA genes (for subtypes A, C, D2, E, F, and G) have been cloned, their relationship to DNA repair remains unknown. In the current study, we show that a nuclear complex containing the FANCA, FANCC, FANCF, and FANCG proteins is required for the activation of the FANCD2 protein to a monoubiquitinated isoform. In normal (non-FA) cells, FANCD2 is monoubiquitinated in response to DNA damage and is targeted to nuclear foci (dots). Activated FANCD2 protein colocalizes with the breast cancer susceptibility protein, BRCA1, in ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes. The FANCD2 protein, therefore, provides the missing link between the FA protein complex and the cellular BRCA1 repair machinery. Disruption of this pathway results in the cellular and clinical phenotype common to all FA subtypes.