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

Y Pereg, D Shkedy, P de Graaf, E Meulmeester, M Edelson-Averbukh, M Salek, S Biton, AFAS Teunisse, WD Lehmann, AG Jochemsen, Y Shiloh*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-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
    Publication statusPublished - 5 Apr 2005

    Keywords

    • ataxia-telangiectasia
    • DNA damage response
    • p53
    • protein degradation
    • DOUBLE-STRAND BREAKS
    • SIGNALING PATHWAYS
    • ATAXIA-TELANGIECTASIA
    • P53
    • MDM2
    • STRESS
    • ACTIVATION
    • MECHANISMS
    • KINASES
    • CANCER

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