Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage

Yaron Pereg, Dganit Shkedy, Petra De Graaf, Erik Meulmeester, Marina Edelson-Averbukh, Mogjiborahman Salek, Sharon Biton, Amina F.A.S. Teunisse, Wolf D. Lehmann, Aart G. Jochemsen, Yosef Shiloh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 DSB 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.

Original languageEnglish
Pages (from-to)5056-5061
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number14
DOIs
StatePublished - 5 Apr 2005

Funding

FundersFunder number
National Institute of Neurological Disorders and StrokeR01NS031763

    Keywords

    • Ataxia-telangiectasia
    • DNA damage response
    • Protein degradation
    • p53

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