Rice W G, Hillyer C D, Harten B, Schaeffer C A, Dorminy M, Lackey D A, Kirsten E, Mendeleyev J, Buki K G, Hakam A
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322.
Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7703-7. doi: 10.1073/pnas.89.16.7703.
6-Nitroso-1,2-benzopyrone and 3-nitrosobenzamide, two C-nitroso compounds that inactivate the eukaryotic nuclear protein poly(ADP-ribose) polymerase [NAD+:poly(adenosine diphosphate D-ribose) ADP-D-ribosyltransferase, ADPRT, EC 2.4.2.30] at one zinc-finger site, completely suppressed the proliferation of leukemic and other malignant human cells and subsequently produced cell death. Tumoricidal concentrations of the drugs were relatively harmless to normal bone marrow progenitor cells and to superoxide formation by neutrophil granulocytes. The cellular mechanism elicited by the C-nitroso compounds consists of apoptosis due to DNA degradation by the nuclear calcium/magnesium-dependent endonuclease. This endonuclease is maintained in a latent form by poly(ADP-ribosyl)ation, but inactivation of ADPRT by C-nitroso drugs derepresses the DNA-degrading activity. ADPRT is thus identified as a critical regulatory enzyme component of a DNA-binding multiprotein system that plays a central function in defining DNA structures in the intact cell.
6-亚硝基-1,2-苯并吡喃酮和3-亚硝基苯甲酰胺这两种C-亚硝基化合物，能在一个锌指位点使真核细胞核蛋白聚（ADP-核糖）聚合酶[烟酰胺腺嘌呤二核苷酸：聚（腺苷二磷酸-D-核糖）ADP-D-核糖基转移酶，ADPRT，EC 2.4.2.30]失活，它们完全抑制白血病细胞和其他恶性人类细胞的增殖，并随后导致细胞死亡。药物的杀肿瘤浓度对正常骨髓祖细胞和中性粒细胞形成超氧化物相对无害。C-亚硝基化合物引发的细胞机制包括由于核钙/镁依赖性核酸内切酶导致的DNA降解而引起的细胞凋亡。这种核酸内切酶通过聚（ADP-核糖基）化保持潜伏形式，但C-亚硝基药物使ADPRT失活会解除对DNA降解活性的抑制。因此，ADPRT被确定为一个DNA结合多蛋白系统的关键调节酶成分，该系统在完整细胞中定义DNA结构方面发挥着核心作用。
