Berger N A, Sims J L, Catino D M, Berger S J
Princess Takamatsu Symp. 1983;13:219-26.
Treatment of cells with DNA damaging agents results in a dose dependent decrease in NAD+ and ATP pool sizes. The decrease in NAD+ is associated with the activation of poly(ADP-ribose) polymerase and the decrease in ATP is consequent to the fall in NAD+. Depletion of both NAD+ and ATP can be blocked or retarded by inhibitors of poly(ADP-ribose) polymerase. Both the stimulation of poly(ADP-ribose) synthesis and the effect of enzyme inhibitors have been confirmed in intact cells by using enzymatic cycling techniques to measure the disappearance of NAD+ and high pressure liquid chromatography (HPLC) to measure fluctuations in polymer levels. As a consequence of the depletion of NAD+ and ATP pools, cells exhibit a marked impairment in their ability to conduct all energy dependent functions. Thus cells treated with high levels of DNA damaging agents exhibit severe suppression of DNA replication and repair, RNA synthesis and protein synthesis. The use of inhibitors of poly(ADP-ribose) polymerase to prevent the depletion of NAD+ and ATP partially restores the cells' ability to conduct DNA, RNA, and protein synthesis. This preservation of the NAD+ and ATP pools accounts for the recent observations that inhibitors of poly(ADP-ribose) stimulate the level of DNA repair synthesis in cells treated with high levels of DNA damaging agents. We have also examined cells from patients with several of the disorders of DNA repair and have found that cells from patients with Fanconi's anemia have lower than normal NAD+ levels.(ABSTRACT TRUNCATED AT 250 WORDS)
用DNA损伤剂处理细胞会导致NAD⁺和ATP池大小呈剂量依赖性降低。NAD⁺的降低与聚（ADP - 核糖）聚合酶的激活有关，而ATP的降低是NAD⁺下降的结果。聚（ADP - 核糖）聚合酶抑制剂可阻断或延缓NAD⁺和ATP的耗竭。通过使用酶循环技术测量NAD⁺的消失以及高压液相色谱法（HPLC）测量聚合物水平的波动，已在完整细胞中证实了聚（ADP - 核糖）合成的刺激作用和酶抑制剂的效果。由于NAD⁺和ATP池的耗竭，细胞进行所有能量依赖性功能的能力出现明显受损。因此，用高水平DNA损伤剂处理的细胞表现出DNA复制和修复、RNA合成及蛋白质合成的严重抑制。使用聚（ADP - 核糖）聚合酶抑制剂来防止NAD⁺和ATP的耗竭可部分恢复细胞进行DNA、RNA和蛋白质合成的能力。NAD⁺和ATP池的这种维持解释了最近的观察结果，即聚（ADP - 核糖）抑制剂可刺激用高水平DNA损伤剂处理的细胞中的DNA修复合成水平。我们还检查了患有几种DNA修复障碍疾病患者的细胞，发现范可尼贫血患者的细胞NAD⁺水平低于正常水平。（摘要截短至250字）
