Mdm2 promotes genetic instability and transformation independent of p53
Mdm2 promotes genetic instability and transformation independent of p53
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DOI：
10.1128/mcb.01584-07
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发表时间：
2008-08-01
影响因子：
5.3
通讯作者：
Eischen, Christine A.
中科院分区：
文献类型：
--
作者：
Bouska, Alyssa;Lushnikova, Tamara;Eischen, Christine A.
mdm 2是肿瘤抑制因子p53的调节因子，在人类恶性肿瘤中经常过度表达。mdm 2也有未解决的，p53非依赖性的功能，有助于肿瘤发生。在这里，我们表明，增加Mdm 2的表达诱导染色体/染色单体断裂和延迟DNA双链断裂修复的细胞缺乏p53，但不是在细胞中的突变形式的Nbs 1，Mre 11/Rad 50/Nbs 1 DNA修复复合物的一个组成部分。Mdm 2的31个氨基酸的区域是必需的结合到Nbs 1。Mdm 2的Nbs 1结合结构域中保守氨基酸的突变抑制了Mdm 2-Nbs 1缔合，并阻止了Mdm 2延迟H2 AX和ATM-S/TQ位点的磷酸化、DNA断裂的修复和DNA损伤灶的消退。类似地，Nbs 1的Mdm 2结合结构域中的8个氨基酸的突变抑制了Mdm 2-Nbs 1相互作用并阻断了Mdm 2延迟DNA断裂修复的能力。Nbs 1和ATM，但不是泛素连接酶活性的Mdm 2，是必要的，以抑制DNA断裂修复。只有具有完整的Nbs 1结合结构域的Mdm 2能够增加染色体/染色单体断裂的频率和缺乏p53的细胞的转化效率。因此，Mdm 2与Nbs 1的相互作用抑制DNA断裂修复，导致染色体不稳定和随后的转化，这是独立于p53。
Mdm2, a regulator of the tumor suppressor p53, is frequently overexpressed in human malignancies. Mdm2 also has unresolved, p53-independent functions that contribute to tumorigenesis. Here, we show that increased Mdm2 expression induced chromosome/chromatid breaks and delayed DNA double-strand break repair in cells lacking p53 but not in cells with a mutant form of Nbs1, a component of the Mre11/Rad50/Nbs1 DNA repair complex. A 31-amino-acid region of Mdm2 was necessary for binding to Nbs1. Mutation of conserved amino acids in the Nbs1 binding domain of Mdm2 inhibited Mdm2-Nbs1 association and prevented Mdm2 from delaying phosphorylation of H2AX and ATM-S/TQ sites, repair of DNA breaks, and resolution of DNA damage foci. Similarly, the mutation of eight amino acids in the Mdm2 binding domain of Nbs1 inhibited Mdm2-Nbs1 interaction and blocked the ability of Mdm2 to delay DNA break repair. Both Nbs1 and ATM, but not the ubiquitin ligase activity of Mdm2, were necessary to inhibit DNA break repair. Only Mdm2 with an intact Nbs1 binding domain was able to increase the frequency of chromosome/chromatid breaks and the transformation efficiency of cells lacking p53. Therefore, the interaction of Mdm2 with Nbs1 inhibited DNA break repair, leading to chromosome instability and subsequent transformation that was independent of p53.