Tumor suppressor p53 binding protein 1 (53BP1) is involved in DNA damage-signaling pathways.
Tumor suppressor p53 binding protein 1 (53BP1) is involved in DNA damage-signaling pathways.
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DOI：
10.1083/jcb.153.3.613
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发表时间：
2001-04-30
期刊：
影响因子：
--
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Rappold I;Iwabuchi K;Date T;Chen J
肿瘤抑制因子p53结合蛋白1（53 BP 1）与p53的DNA结合结构域结合并增强p53介导的转录激活。53 BP 1含有两个乳腺癌易感基因1 COOH末端（BRCT）基序，其存在于参与DNA修复和/或DNA损伤信号通路的几种蛋白中。因此，我们研究了53 BP 1在DNA损伤信号通路中的潜在作用。在这里，我们报告说，53 BP 1变得过度磷酸化，并形成离散的核灶，以响应DNA损伤。这些病灶在所有时间点与磷酸化H2 AX（γ-H2 AX）共定位，其先前已被证明定位于DNA链断裂位点。53 BP 1焦点的形成不限于γ-辐射，也可在UV辐射以及羟基脲、喜树碱、依托泊苷和甲磺酸甲酯处理后检测到。一些观察结果表明，53 BP 1的调节共济失调毛细血管扩张突变（ATM）DNA损伤后。首先，与表达野生型ATM的细胞相比，ATM缺陷型细胞显示没有53 BP 1过度磷酸化，并且响应于γ辐射的53 BP 1灶形成减少。第二，渥曼青霉素处理强烈抑制γ-辐射诱导的过度磷酸化和53 BP 1的灶形成。第三，53 BP 1在体外容易被ATM磷酸化。综上所述，这些结果表明，53 BP 1是一种ATM底物，在哺乳动物细胞中早期参与DNA损伤信号通路。
The tumor suppressor p53 binding protein 1 (53BP1) binds to the DNA-binding domain of p53 and enhances p53-mediated transcriptional activation. 53BP1 contains two breast cancer susceptibility gene 1 COOH terminus (BRCT) motifs, which are present in several proteins involved in DNA repair and/or DNA damage–signaling pathways. Thus, we investigated the potential role of 53BP1 in DNA damage–signaling pathways. Here, we report that 53BP1 becomes hyperphosphorylated and forms discrete nuclear foci in response to DNA damage. These foci colocalize at all time points with phosphorylated H2AX (γ-H2AX), which has been previously demonstrated to localize at sites of DNA strand breaks. 53BP1 foci formation is not restricted to γ-radiation but is also detected in response to UV radiation as well as hydroxyurea, camptothecin, etoposide, and methylmethanesulfonate treatment. Several observations suggest that 53BP1 is regulated by ataxia telangiectasia mutated (ATM) after DNA damage. First, ATM-deficient cells show no 53BP1 hyperphosphorylation and reduced 53BP1 foci formation in response to γ-radiation compared with cells expressing wild-type ATM. Second, wortmannin treatment strongly inhibits γ-radiation–induced hyperphosphorylation and foci formation of 53BP1. Third, 53BP1 is readily phosphorylated by ATM in vitro. Taken together, these results suggest that 53BP1 is an ATM substrate that is involved early in the DNA damage–signaling pathways in mammalian cells.
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