| Autor: |
Pereg, Yaron, Shkedy, Dganit, de Graaft, Petra, Meulmeester, Erik, Edelson-Averbukh, Marina, Salek, Mogjiborahman, Biton, Sharon, Teunisse, Amina F. A. S., Lehmann, Wolf D., Jochemsen, Aart G., Shiloh, Yosef |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 4/5/2005, Vol. 102 Issue 14, p5056-5061, 6p |
| Abstrakt: |
Maintenance of genomic stability depends on the DNA damage response, an extensive signaling network that is activated by DNA lesions such as double-strand breaks (DSBs). The primary activator of the mammalian NB response is the nuclear protein kinase ataxia-telangiectasia, mutated (ATM), which phosphorylates key players in various arms of this network. The activation and stabilization of the p53 protein play a major role in the DNA damage response and are mediated by ATM-dependent posttranslational modifications of p53 and Mdm2, a ubiquitin ligase of p53. p53's response to DNA damage also depends on Mdm2-dependent proteolysis of Mdmx, a homologue of Mdm2 that represses p53's transactivation function. Here we show that efficient damage- induced degradation of human Hdmx depends on functional ATM and at least three sites on the Hdmx that are phosphorylated in response to DSBs. One of these sites, S403, is a direct ATM target. Accordingly, each of these sites is important for Hdm2-mediated ubiquitination of Hdmx after DSB induction. These results demonstrate a sophisticated mechanism whereby ATM fine-tunes the optimal activation of p53 by simultaneously modifying each player in the process. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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