Aven-Dependent Activation of ATM Following DNA Damage

Jessie Yanxiang Guo, Ayumi Yamada, Taisuke Kajino, Judy Qiju Wu, Wanli Tang, Christopher D. Freel, Junjie Feng, B. Nelson Chau, Michael Zhuo Wang, Seth S. Margolis, Hae Yong Yoo, Xiao Fan Wang, William G. Dunphy, Pablo M. Irusta, J. Marie Hardwick, Sally Kornbluth

Research output: Contribution to journalArticlepeer-review

Abstract

Background: In response to DNA damage, cells undergo either cell-cycle arrest or apoptosis, depending on the extent of damage and the cell's capacity for DNA repair. Cell-cycle arrest induced by double-stranded DNA breaks depends on activation of the ataxia-telangiectasia (ATM) protein kinase, which phosphorylates cell-cycle effectors such as Chk2 and p53 to inhibit cell-cycle progression. ATM is recruited to double-stranded DNA breaks by a complex of sensor proteins, including Mre11/Rad50/Nbs1, resulting in autophosphorylation, monomerization, and activation of ATM kinase. Results: In characterizing Aven protein, a previously reported apoptotic inhibitor, we have found that Aven can function as an ATM activator to inhibit G2/M progression. Aven bound to ATM and Aven overexpressed in cycling Xenopus egg extracts prevented mitotic entry and induced phosphorylation of ATM and its substrates. Immunodepletion of endogenous Aven allowed mitotic entry even in the presence of damaged DNA, and RNAi-mediated knockdown of Aven in human cells prevented autophosphorylation of ATM at an activating site (S1981) in response to DNA damage. Interestingly, Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. Conclusions: These results identify Aven as a new ATM activator and describe a positive feedback loop operating between Aven and ATM. In aggregate, these findings place Aven, a known apoptotic inhibitor, as a critical transducer of the DNA-damage signal.

Original languageEnglish (US)
Pages (from-to)933-942
Number of pages10
JournalCurrent Biology
Volume18
Issue number13
DOIs
StatePublished - Jul 8 2008

Keywords

  • DNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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