DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress
DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress
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DOI：
10.1371/journal.pgen.1002557
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发表时间：
2012-03-01
期刊：
影响因子：
4.5
通讯作者：
Digweed, Martin
中科院分区：
文献类型：
--
作者：
Krenzlin, Harald;Demuth, Ilja;Digweed, Martin
Nijmegen breaking Syndrome （NBS）是一种常染色体隐性遗传不稳定综合征，是由编码nibrin蛋白的NBN基因发生次型突变引起的。Nibrin是处理DNA双链断裂所必需的MRE11/RAD50/NBN （MRN）复合体的一个完整成员。NBS的主要特征是免疫缺陷和血液系统恶性肿瘤的极高发病率。最近对条件零突变小鼠的研究表明，由于DSB加工受损，氧化还原稳态受到干扰。显然，这可能会导致DNA损伤、染色体不稳定和癌症的发生。我们发现，在完全没有nibrin的零突变小鼠细胞中，暴露于诱变剂几个小时后，活性氧的水平很高。我们进一步表明，与小鼠零突变细胞不同，NBS患者细胞具有截断的nibrin蛋白，在DNA损伤后也具有高水平的活性氧，并且这种增加的氧化应激是由于链断裂传感器Poly（adp -核糖）聚合酶的过度激活导致NAD+的耗竭引起的。使用特定的聚（adp -核糖）聚合酶抑制剂可以逆转聚（adp -核糖）聚合酶的过度活化和ROS水平的升高。NBS患者中极高的恶性肿瘤发生率是原发性DSB修复缺陷与继发性DNA氧化损伤共同作用的结果。
Nijmegen Breakage Syndrome (NBS), an autosomal recessive genetic instability syndrome, is caused by hypomorphic mutation of the NBN gene, which codes for the protein nibrin. Nibrin is an integral member of the MRE11/RAD50/NBN (MRN) complex essential for processing DNA double-strand breaks. Cardinal features of NBS are immunodeficiency and an extremely high incidence of hematological malignancies. Recent studies in conditional null mutant mice have indicated disturbances in redox homeostasis due to impaired DSB processing. Clearly this could contribute to DNA damage, chromosomal instability, and cancer occurrence. Here we show, in the complete absence of nibrin in null mutant mouse cells, high levels of reactive oxygen species several hours after exposure to a mutagen. We show further that NBS patient cells, which unlike mouse null mutant cells have a truncated nibrin protein, also have high levels of reactive oxygen after DNA damage and that this increased oxidative stress is caused by depletion of NAD+ due to hyperactivation of the strand-break sensor, Poly(ADP-ribose) polymerase. Both hyperactivation of Poly(ADP-ribose) polymerase and increased ROS levels were reversed by use of a specific Poly(ADP-ribose) polymerase inhibitor. The extremely high incidence of malignancy among NBS patients is the result of the combination of a primary DSB repair deficiency with secondary oxidative DNA damage.