Poly ADP-ribosylation:: A DNA break signal mechanism
Poly ADP-ribosylation:: A DNA break signal mechanism
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DOI：
10.1023/a:1006975002262
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发表时间：
1999-03-01
影响因子：
4.3
通讯作者：
Auer, B
中科院分区：
文献类型：
--
作者：
Althaus, FR;Kleczkowska, HE;Auer, B
最近从转基因敲除小鼠获得的证据表明，聚（ADP-核糖）聚合酶（PARP）在DNA断裂过程中不起直接作用[1，2]。然而，PARP的催化或DNA切口结合功能的失活在细胞存活、姐妹染色单体交换和细胞凋亡水平上影响细胞对遗传毒素的反应[2，3]。在本报告中，我们概念化了PARP是DNA断裂信号机制的一部分的想法[4，5]。体外筛选研究揭示了一个蛋白质家族的存在，该家族含有约22个氨基酸的聚合物结合基序。该基序存在于p53蛋白以及MARCKS中，MARCKS是一种参与肌动蛋白细胞骨架调节的蛋白。生物化学分析表明，这些序列在体外直接被PARP相关聚合物靶向，这改变了p53和MARCKS蛋白的几种分子功能。来自转基因小鼠的PARP缺陷敲除小鼠被发现表现出与改变的DNA损伤信号传导相容的几种表型特征，如下调和缺乏p53蛋白对遗传毒素的反应性，以及与MARCKS相关的细胞骨架功能障碍相容的形态学变化。敲除表型可以通过PARP基因的稳定表达来挽救。我们认为，PARP相关的聚合物可能会招募信号蛋白的DNA断裂的网站和重新编程他们的功能。
Recent evidence obtained with transgenic knockout mice suggests that the enzyme poly(ADP-ribose)polymerase (PARP) does not play a direct role in DNA break processing [1, 2]. Nevertheless, inactivation of the catalytic or the DNA nick-binding functions of PARP affects cellular responses to genotoxins at the level of cell survival, sister chromatid exchanges and apoptosis [2, 3]. In the present report, we conceptualize the idea that PARP is part of a DNA break signal mechanism [4, 5]. In vitro screening studies revealed the existence of a protein family containing a polymer-binding motif of about 22 amino acids. This motif is present in p53 protein as well as in MARCKS, a protein involved in the regulation of the actin cytoskeleton. Biochemical analyses showed that these sequences are directly targeted by PARP-associated polymers in vitro, and this alters several molecular functions of p53- and MARCKS protein. PARP-deficient knockout mice from transgenic mice were found to exhibit several phenotypic features compatible with altered DNA damage signaling, such as downregulation and lack of responsiveness of p53 protein to genotoxins, and morphological changes compatible with MARCKS-related cytoskeletal dysfunction. The knockout phenotype could be rescued by stable expression of the PARP gene. We propose that PARP-associated polymers may recruit signal proteins to sites of DNA breakage and reprogram their functions.