Human α spectrin II and the Fanconi anemia proteins FANCA and FANCC interact to form a nuclear complex
Human α spectrin II and the Fanconi anemia proteins FANCA and FANCC interact to form a nuclear complex
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DOI：
10.1074/jbc.274.46.32904
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发表时间：
1999-11-12
影响因子：
4.8
通讯作者：
Lambert, MW
中科院分区：
文献类型：
--
作者：
McMahon, LW;Walsh, CE;Lambert, MW
范可尼贫血（FA）是一种遗传性疾病，其特征是骨髓衰竭、先天性异常、癌症易感性和对DNA链间交联剂的明显细胞超敏反应，这与修复这种损伤的能力缺陷有关。我们之前已经发现了一种大约230 kda的蛋白质存在。正常人类淋巴母细胞样细胞中的一种核蛋白复合体，参与DNA链间交联的修复，并在FA-A细胞核中显示出水平降低。FANCA基因似乎在该蛋白的稳定性或表达中起作用。我们现在表明p230是一种众所周知的结构蛋白，人ct谱蛋白II (α SpII Sigma*)， α SpII Sigma*的水平不仅在FA- a细胞中显著降低，而且在FA- b、FA- c和FA- d细胞（即所有FA细胞系）中也显著降低，这表明这些FA蛋白在α SpII Sigma*的稳定性或表达中起作用。这些研究还表明，α SpII Sigma*在细胞核内与FANCA和FANCC蛋白形成复合物。因此，α SpII Sigma*可能作为一种支架来排列或增强FA蛋白与参与DNA修复的蛋白之间的相互作用。这些结果表明FA代表了一种缺乏α SpII Sigma*的疾病。
Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure, congenital abnormalities, cancer susceptibility, and a marked cellular hypersensitivity to DNA interstrand cross-linking agents, which correlates with a defect in ability to repair this type of damage, We have previously identified an approximately 230-kDa protein present, in a nuclear protein complex in normal human lymphoblastoid cells that is involved in repair of DNA interstrand cross-links and shows reduced levels in FA-A cell nuclei. The FANCA gene appears to play a role in the stability or expression of this protein. me now show that p230 is a well known structural protein, human ct spectrin II (alpha SpII Sigma*), and that levels of alpha SpII Sigma* are not only significantly reduced in FA-A cells but also in FA-B, FA-C and FA-D cells (i.e. in all FA cell Lines tested), suggesting a role for these FA proteins in the stability or expression of alpha SpII Sigma*. These studies also show that alpha SpII Sigma* forms a complex in the nucleus with the FANCA and FANCC proteins. alpha SpII Sigma* may thus act as a scaffold to align or enhance interactions between FA proteins and proteins involved in DNA repair. These results suggest that FA represents a disorder in which there is a deficiency in alpha SpII Sigma*.