Poly(ADP-ribose) binds to specific domains of p53 and alters its DNA binding functions
Poly(ADP-ribose) binds to specific domains of p53 and alters its DNA binding functions
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DOI：
10.1074/jbc.273.19.11839
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发表时间：
1998-05-08
影响因子：
4.8
通讯作者：
Althaus, FR
中科院分区：
文献类型：
--
作者：
Malanga, M;Pleschke, JM;Althaus, FR
DNA链断裂是核酶聚（ADP核糖）聚合酶（PARP; E.C. 2.4.2.30）和肿瘤抑制蛋白p53。这两种蛋白质都结合并响应DNA断裂，并且都在DNA损伤信号传导中发挥作用。在哺乳动物细胞中已经证明了这些蛋白质之间的临时共定位和复合物形成。在这里，我们表明，自由和聚（ADP-核糖）聚合酶结合的ADP-核糖聚合物靶向p53蛋白的三个结构域的强非共价相互作用。聚合物结合位点可以定位到p53的序列特异性核心DNA结合结构域中的两个氨基酸序列（氨基酸位置153-178和231-253）和寡聚化结构域中的另一个氨基酸序列（氨基酸326-348）。在迁移率改变实验中，聚（ADP-核糖）有效地防止和逆转p53结合p53的回文序列的共识。此外，聚（ADP-核糖）也干扰p53的DNA单链末端结合。结果表明，ADP-核糖聚合物可能在调节p53的DNA结合特性中发挥作用。
DNA strand breaks are potential interaction sites for the nuclear enzyme poly(ADP ribose) polymerase (PARP; E.C. 2.4.2.30) and the tumor suppressor protein p53. Both proteins bind and respond to DNA breaks and both play a role in DNA damage signaling. A temporary colocalization and complex formation between these proteins has been demonstrated in mammalian cells. Here we show that free and poly(ADP-ribose) polymerase-bound ADP-ribose polymers target three domains in p53 protein for strong noncovalent interactions. The polymer binding sites could be mapped to two amino acid sequences in the sequence-specific core DNA binding domain of p53 (amino acid positions 153-178 and 231-253) and another one in the oligomerization domain (amino acids 326-348). In mobility shift experiments, poly(ADP-ribose) effectively prevented and reversed p53 binding to the palindromic p53 consensus sequence. Additionally, poly(ADP-ribose) also interfered with the DNA single strand end binding of p53. The results suggest that ADP-ribose polymers could play a role in regulating the DNA binding properties of p53.