The Fanconi anemia complementation group C gene product: structural evidence of multifunctionality
The Fanconi anemia complementation group C gene product: structural evidence of multifunctionality
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DOI：
10.1182/blood.v98.5.1392
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发表时间：
2001-09-01
期刊：
影响因子：
20.3
通讯作者：
Bagby, GC
中科院分区：
文献类型：
--
作者：
Pang, QS;Christianson, TA;Bagby, GC
范可尼贫血（FA）C组基因产物（FANCC）的功能是保护细胞免受交联剂的细胞毒性和遗传毒性作用。FANCC也是STAT 1响应细胞因子和生长因子的最佳激活所必需的，并且通过调节双链RNA依赖性蛋白激酶的活性来抑制精氨酸诱导的细胞凋亡。由于并非所有FANCC突变都影响STAT 1激活，因此认为FANCC的交联剂抗性功能取决于与FANCC的细胞因子信号传导功能所需的结构元件不同的结构元件。结构-功能研究旨在验证这一概念。在FANCC的3个高度保守的基序中产生了6个独立的丙氨酸取代突变。所有突变体都补充了FA-C细胞的丝裂霉素C（MMC）超敏表型，并纠正了FA-C突变细胞中FANCD 2的异常翻译后激活。然而，突变体S249 A和E251 A中的2个未能纠正缺陷性STAT 1激活。携带这2个突变体的FA-C淋巴母细胞在STAT 1向干扰素γ（IFN-γ）受体的募集中表现出缺陷，并且携带S249 A和E251 A突变的GST融合蛋白在刺激的淋巴母细胞中对于STAT 1是不太有效的结合伴侣。这些相同的突变未能补充FA-C细胞对肿瘤坏死因子-α（TNF-α）和IFN-α的特征性超敏凋亡反应。携带天然存在的FANCC突变（322 delG）的细胞保留了这一保守区域，表现出正常的STAT 1激活，但对MMC保持高敏感性。结论是FANCC的中心高度保守结构域是与STAT 1功能相互作用所必需的，并且STAT 1相关功能所需的结构元件不同于对交联剂的遗传毒性反应所需的结构元件。携带del 322 G突变的细胞的信号传导能力的保存可能解释了与该突变相关的骨髓衰竭的严重程度降低和较晚发作。(C)2001年，美国血液学会。
The Fanconi anemia (FA) group C gene product (FANCC) functions to protect cells from cytotoxic and genotoxic effects of cross-linking agents. FANCC is also required for optimal activation of STAT1 in response to cytokine and growth factors and for suppressing cytokine-induced apoptosis by modulating the activity of double-stranded RNA-dependent protein kinase. Because not all FANCC mutations affect STAT1 activation, the hypothesis was considered that cross-linker resistance function of FANCC depends on structural elements that differ from those required for the cytokine signaling functions of FANCC. Structure-function studies were designed to test this notion. Six separate alanine-substituted mutations were generated In 3 highly conserved motifs of FANCC. All mutants complemented mitomycin C (MMC) hypersensitive phenotype of FA-C cells and corrected aberrant posttranslational activation of FANCD2 in FA-C mutant cells. However, 2 of the mutants, S249A and E251 A, failed to correct defective STAT1 activation. FA-C lymphoblasts carrying these 2 mutants demonstrated a defect In recruitment of STAT1 to the interferon gamma (IFN-gamma) receptor and GST-fusion proteins bearing S249A and E251A mutations were less efficient binding partners for STAT1 in stimulated lymphoblasts. These same mutations failed to complement the characteristic hypersensitive apoptotic responses of FA-C cells to tumor necrosis factor-alpha (TNF-alpha) and IFN-alpha. Cells bearing a naturally occurring FANCC mutation (322delG) that preserves this conserved region showed normal STAT1 activation but remained hypersensitive to MMC. The conclusion Is that a central highly conserved domain of FANCC Is required for functional interaction with STAT1 and that structural elements required for STAT1-related functions differ from those required for genotoxic responses to cross-linking agents. Preservation of signaling capacity of cells bearing the del322G mutation may account for the reduced severity and later onset of bone marrow failure associated with this mutation. (C) 2001 by The American Society of Hematology.