TY - JOUR
T1 - Aven-Dependent Activation of ATM Following DNA Damage
AU - Guo, Jessie Yanxiang
AU - Yamada, Ayumi
AU - Kajino, Taisuke
AU - Wu, Judy Qiju
AU - Tang, Wanli
AU - Freel, Christopher D.
AU - Feng, Junjie
AU - Chau, B. Nelson
AU - Wang, Michael Zhuo
AU - Margolis, Seth S.
AU - Yoo, Hae Yong
AU - Wang, Xiao Fan
AU - Dunphy, William G.
AU - Irusta, Pablo M.
AU - Hardwick, J. Marie
AU - Kornbluth, Sally
N1 - Funding Information:
We are grateful to James Edwin Hall (UNC Chapel Hill) for mass-spectrometry resources. We thank Jen Perry and Carrie Johnson for reading and discussing the manuscript. This work was supported by National Institutes of Health grants ROI GM67225 and RO1 CA102707 to S.K., RO1 NS34704 to J.M.H., RO1 AI54952 to P.I., and RO1 GM043974, RO1 GM070891 to W.G.D, and RO1 CA123250 to X.W.
PY - 2008/7/8
Y1 - 2008/7/8
N2 - 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.
AB - 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.
KW - DNA
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U2 - 10.1016/j.cub.2008.05.045
DO - 10.1016/j.cub.2008.05.045
M3 - Article
C2 - 18571408
AN - SCOPUS:45849103487
SN - 0960-9822
VL - 18
SP - 933
EP - 942
JO - Current Biology
JF - Current Biology
IS - 13
ER -