Nargi-Aizenman Jennifer L, Simbulan-Rosenthal Cynthia M, Kelly Tara A, Smulson Mark E, Griffin Diane E
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns hopkins University, Baltimore, Maryland 21205, USA.
Virology. 2002 Feb 1;293(1):164-71. doi: 10.1006/viro.2001.1253.
Poly(ADP-ribose) polymerase-1 (PARP-1) is a chromatin-associated enzyme that is activated by DNA strand breaks and catalyzes the transfer of ADP-ribose groups from NAD to itself and other nuclear proteins. Although caspase-mediated PARP-1 cleavage occurs during almost all forms of apoptosis, the contribution of PARP-1 activation and cleavage to this cell death process remains unclear. Using immortalized fibroblasts from wild-type (PARP-1(+/+)) and PARP-1 knockout (PARP-1(-/-)) mice, and a mouse neuroblastoma cell line (N18), the role that poly(ADP-ribosyl)ation plays in Sindbis virus (SV)-induced apoptosis was examined. Robust PARP-1 activation occurred in SV-infected cells prior to morphologic changes associated with apoptotic cell death and PARP-1 activity ceased simultaneously with caspase-3 activation and PARP-1 proteolysis. PARP-1 activity was maximal before detectable DNA fragmentation, but was absent when DNA damage was most intense. SV and staurosporine-induced cell death was delayed in fibroblasts lacking PARP-1 activity, suggesting that PARP-1 activation contributes to apoptotic cell death induced by these stimuli. SV replication was not affected by lack of PARP-1 activity, but DNA fragmentation and caspase-3 activation were delayed and occurred at lower levels in PARP-1-deficient fibroblasts. Early virus-induced PARP-1 activation may represent a novel way by which cells signal to the nucleus to regulate protein function by poly(ADP-ribosyl)ation in response to virus infection.
聚（ADP - 核糖）聚合酶 -1（PARP -1）是一种与染色质相关的酶，可被DNA链断裂激活，并催化ADP - 核糖基团从NAD转移至自身及其他核蛋白。尽管在几乎所有形式的细胞凋亡过程中都会发生半胱天冬酶介导的PARP -1裂解，但PARP -1激活和裂解对这一细胞死亡过程的作用仍不清楚。利用来自野生型（PARP -1(+/+)）和PARP -1基因敲除（PARP -1(-/-)）小鼠的永生化成纤维细胞以及小鼠神经母细胞瘤细胞系（N18），研究了聚（ADP - 核糖基）化在辛德毕斯病毒（SV）诱导的细胞凋亡中所起的作用。在与凋亡细胞死亡相关的形态学变化之前，SV感染的细胞中发生了强烈的PARP -1激活，并且PARP -1活性在半胱天冬酶 -3激活和PARP -1蛋白水解同时停止。PARP -1活性在可检测到的DNA片段化之前达到最大值，但在DNA损伤最严重时消失。在缺乏PARP -1活性的成纤维细胞中，SV和星形孢菌素诱导的细胞死亡延迟，这表明PARP -1激活有助于这些刺激诱导的凋亡细胞死亡。PARP -1活性的缺乏不影响SV复制，但DNA片段化和半胱天冬酶 -3激活延迟，并且在PARP -1缺陷的成纤维细胞中发生的水平较低。早期病毒诱导的PARP -1激活可能代表了一种新的方式，通过这种方式细胞向细胞核发出信号，以响应病毒感染通过聚（ADP - 核糖基）化来调节蛋白质功能。
