Role for 53BP1 Tudor Domain Recognition of p53 Dimethylated at Lysine 382 in DNA Damage Signaling
Role for 53BP1 Tudor Domain Recognition of p53 Dimethylated at Lysine 382 in DNA Damage Signaling
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DOI：
10.1074/jbc.m806020200
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发表时间：
2008-12-12
影响因子：
4.8
通讯作者：
Gozani, Or
中科院分区：
文献类型：
--
作者：
Kachirskaia, Ioulia;Shi, Xiaobing;Gozani, Or
赖氨酸甲基化修饰组蛋白是一种主要的染色质调节机制（Shi， Y., and Whet-stine， J. R. (2007) Mol. Cell 25, 1-14）。最近，赖氨酸甲基化也被证明在调节非组蛋白中发挥作用，包括肿瘤抑制蛋白p53 (Huang， J., and Berger， S. L. (2008) Curr。当今。麝猫。发展。18,152-158)。在这里，我们发现了一个新的p53物种，它在赖氨酸382 （p53K382me2）上被二甲基化，并表明DNA损伤反应介质53BP1的串联都铎结构域作为该标记的“效应”。我们证明53BP1串联Tudor结构域对p53K382me2具有相对于其他几种赖氨酸甲基化位点和饱和状态的选择性。p53K382me2水平随着DNA损伤而增加，53BP1对这种修饰的识别促进了p53和53BP1之间的相互作用。p53K382me2的产生促进了DNA损伤时p53蛋白的积累，而p53水平的增加需要53BP1。综上所述，我们的研究确定了一种新的p53修饰，展示了53BP1串联都铎结构域的新效应功能，并提供了DNA损伤信号如何被转导以稳定p53的见解。
Modification of histone proteins by lysine methylation is a principal chromatin regulatory mechanism (Shi, Y., and Whet-stine, J. R. (2007) Mol. Cell 25, 1-14). Recently, lysine methylation has been shown also to play a role in regulating non-histone proteins, including the tumor suppressor protein p53 (Huang, J., and Berger, S. L. (2008) Curr. Opin. Genet. Dev. 18, 152-158). Here, we identify a novel p53 species that is dimethylated at lysine 382 (p53K382me2) and show that the tandem Tudor domain of the DNA damage response mediator 53BP1 acts as an "effector" for this mark. We demonstrate that the 53BP1 tandem Tudor domain recognizes p53K382me2 with a selectivity relative to several other protein lysine methylation sites and saturation states. p53K382me2 levels increase with DNA damage, and recognition of this modification by 53BP1 facilitates an interaction between p53 and 53BP1. The generation of p53K382me2 promotes the accumulation of p53 protein that occurs upon DNA damage, and this increase in p53 levels requires 53BP1. Taken together, our study identifies a novel p53 modification, demonstrates a new effector function for the 53BP1 tandem Tudor domain, and provides insight into how DNA damage signals are transduced to stabilize p53.