MTA1 Coregulator Regulates p53 Stability and Function
MTA1 Coregulator Regulates p53 Stability and Function
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DOI：
10.1074/jbc.m109.056499
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发表时间：
2009-12-11
影响因子：
4.8
通讯作者：
Kumar, Rakesh
中科院分区：
文献类型：
--
作者：
Li, Da-Qiang;Reddy, Sirigiri Divijendra Natha;Kumar, Rakesh
虽然转移相关蛋白1（MTA 1）最近已被证明是一种DNA损伤反应蛋白，但其在DNA双链断裂（DSB）修复中作用的潜在机制仍不清楚。在这里，我们表明，MTA 1控制p53的稳定性，通过抑制其泛素化的E3泛素连接酶小鼠双分钟2（Mdm 2）和组成型光形态发生蛋白1（COP 1）。潜在的机制涉及MTA 1与COP 1竞争结合p53和/或使COP 1和Mdm 2不稳定的能力。因此，MTA 1调节p53依赖性转录的p53 R2，一个直接的p53靶基因提供核苷酸修复受损的DNA。MTA 1的缺失损害p53依赖性p53 R2转录并损害DNA修复。有趣的是，这些事件可以通过重新引入MTA 1来逆转，表明MTA 1干扰p53依赖的DNA修复。鉴于MTA 1在人类癌症中广泛上调的事实，这些发现与我们早期发现的MTA 1在DSB修复中的关键作用相结合，表明MTA 1-p53-p53 R2途径在癌细胞DNA损伤反应中的固有作用。
Although metastasis-associated protein 1 (MTA1) has recently been shown as a DNA damage responsive protein, the underlying mechanism for its role in DNA double-strand break (DSB) repair remains unknown. Here, we show that MTA1 controls p53 stability through inhibiting its ubiquitination by E3 ubiquitin ligases mouse double minute 2 (Mdm2) and constitutive photomorphogenic protein 1 (COP1). The underlying mechanisms involve the ability of MTA1 to compete with COP1 to bind to p53 and/or to destabilize COP1 and Mdm2. Consequently, MTA1 regulates the p53-dependent transcription of p53R2, a direct p53 target gene for supplying nucleotides to repair damaged DNA. Depletion of MTA1 impairs p53-dependent p53R2 transcription and compromises DNA repair. Interestingly, these events could be reversed by MTA1 reintroduction, indicating that MTA1 interjects into the p53-dependent DNA repair. Given the fact that MTA1 is widely up-regulated in human cancers, these findings in conjunction with our earlier finding of a crucial role of MTA1 in DSB repair suggest an inherent role of the MTA1-p53-p53R2 pathway in DNA damage response in cancer cells.