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首页> 外文期刊>Biochemistry >Knockdown of μ-Calpain in Fanconi Anemia, FA-A, Cells by siRNA Restores αII Spectrin Levels and Corrects Chromosomal Instability and Defective DNA Interstrand Cross-Link Repair
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Knockdown of μ-Calpain in Fanconi Anemia, FA-A, Cells by siRNA Restores αII Spectrin Levels and Corrects Chromosomal Instability and Defective DNA Interstrand Cross-Link Repair

机译：敲低μ-calpain在Fanconi贫血，FA-A，SiRNA细胞恢复αII光谱水平并校正染色体不稳定性和缺陷DNA Interstrand Cross-Link修复

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摘要

We have previously shown that there is a deficiency in the structural protein, nonerythroid αspectrin (αIISp), in cells from patients with Fanconi anemia (FA). These studies indicate that this deficiency is due to the reduced stability of αIISp and correlates with a decreased level of repair of DNA interstrand crosslinks and chromosomal instability in FA cells. An important factor in the stability of αIISp is its susceptibility to cleavage by the protease, μ-calpain. We hypothesized that an increased level of μ-calpain cleavage of αIISp in FA cells leads to an increased level of breakdown of αIISp and that knocking down expression of μ-calpain in FA cells should restore levels of αIISp and correct a number of the phenotypic defects observed. The results showed that there is increased μ-calpain activity in FA-A, FA-C, FA-D2, FA-F, and FA-G cells that could account for the deficiency in αIISp in these FA cells. Protein interaction studies indicated that FANCA and FANCG bind directly to μ-calpain. We hypothesize that this binding may lead to inhibition of μ-calpain activity in normal cells. Knocking down μ-calpain by siRNA in FA-A cells restored levels of αIISp to normal and reversed a number of the cellular deficiencies in these cells. It corrected the DNA repair defect and the chromosomal instability observed after exposure to a DNA interstrand cross-linking agent. These studies indicate that FA proteins may play an important role in maintaining the stability of αIISp in the cell by regulating its cleavage by μ-calpain. Thus, by reducing the level of breakdown of αIISp in FA cells, we may be able to reverse a number of the cellular deficiencies observed in this disorder.
机译：我们之前已经表明，来自患有FANCONI贫血患者（FA）的细胞中结构蛋白质，壬虫αspectrin（αiisp）存在缺乏症。这些研究表明，这种缺陷是由于αIISP的稳定性降低，并且与发育中的DNA Interstrand交联和染色体不稳定性的修复水平的稳定性降低。 αIISP稳定性的一个重要因素是蛋白酶，μ-Calpain裂解的易感性。我们假设FA细胞中αIISP的μ-Calpain裂解水平增加导致αiISP的崩溃水平增加，并且敲击FA细胞中μ-calpain的表达应恢复αiisp的水平并校正一系列表型缺陷观察到的。结果表明，FA-A，FA-C，FA-D2，FA-F和FA-G细胞中的μ-Calpain活性增加，可以考虑这些FA细胞中αIISP的缺陷。蛋白质相互作用研究表明，FANCA和FANCG直接与μ-CALPAIN结合。我们假设该结合可能导致抑制正常细胞中的μ-Calpain活性。通过Fa-A细胞中的siRNA敲击μ-calpain恢复αiisp水平至正常，并在这些细胞中逆转了许多细胞缺陷。它纠正了在暴露于DNA Interstrand交联剂后观察到的DNA修复缺陷和染色体不稳定性。这些研究表明，通过通过调节μ-calpain的裂解来维持细胞中αIISP的稳定性，FA蛋白可能起着重要作用。因此，通过降低发育细胞中αIISP的分解水平，我们可能能够逆转在该疾病中观察到的多种细胞缺陷。

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  • 来源
    《Biochemistry》 |2010年第26期|共12页
  • 作者

    Pan Zhang; Deepa Sridharan; Muriel W. Lambert;

  • 作者单位

    Department of Pathology and Laboratory Medicine New Jersey Medical School and Graduate School of Biomedical Sciences University of Medicine and Dentistry of New Jersey Newark New Jersey 07103;

    Department of Cancer and DNA Damage Responses Lawrence Berkeley National Laboratory Berkeley CA 94720;

    Department of Pathology and Laboratory Medicine New Jersey Medical School and Graduate School of Biomedical Sciences University of Medicine and Dentistry of New Jersey Newark New Jersey 07103;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

    Knockdown; Anemia; Restores;

    机译：敲低;贫血;恢复;

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