Kun Ernest, Kirsten Eva, Hakam Alaeddin, Bauer Pal I, Mendeleyev Jerome
UCSF Helen Diller Family Comprehensive Cancer Center, Department of Anatomy, University of California, School of Medicine, San Francisco Medical Center, San Francisco, CA 94143, USA.
Biochem Biophys Res Commun. 2008 Feb 8;366(2):568-73. doi: 10.1016/j.bbrc.2007.12.004. Epub 2007 Dec 10.
Our results show that in the intact normal animal cell mitochondrial ATP is directly connected to nuclear PARP-1 by way of a specific adenylate kinase enzymatic path. This mechanism is demonstrated in two models: (a) by its inhibition with a specific inhibitor of adenylate kinase, and (b) by disruption of ATP synthesis through uncoupling of OXPHOS. In each instance the de-inhibited PARP-1 is quantitatively determined by enzyme kinetics. The nuclear binding site of PARP-1 is Topo I, and is identified as a critical "switchpoint" indicating the nuclear element that connects OXPHOS with mRNA synthesis in real time. The mitochondrial-nuclear PARP-1 pathway is not operative in cancer cells.
我们的研究结果表明，在完整的正常动物细胞中，线粒体ATP通过特定的腺苷酸激酶酶促途径直接与细胞核中的PARP-1相连。该机制在两种模型中得到证实：(a) 用腺苷酸激酶的特异性抑制剂对其进行抑制；(b) 通过氧化磷酸化的解偶联破坏ATP合成。在每种情况下，通过酶动力学对去抑制的PARP-1进行定量测定。PARP-1的核结合位点是拓扑异构酶I，并被确定为一个关键的“切换点”，表明实时连接氧化磷酸化与mRNA合成的核元件。线粒体-细胞核PARP-1途径在癌细胞中不起作用。
