ATM activation by oxidative stress

Guo, Zhi, Kozlov, Sergei, Lavin, Martin F., Person, Maria D. and Paull, Tanya T. (2010) ATM activation by oxidative stress. Science, 330 6003: 517-521. doi:10.1126/science.1192912

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Author Guo, Zhi
Kozlov, Sergei
Lavin, Martin F.
Person, Maria D.
Paull, Tanya T.
Title ATM activation by oxidative stress
Journal name Science   Check publisher's open access policy
ISSN 1095-9203
0036-8075
Publication date 2010-10-01
Year available 2010
Sub-type Article (original research)
DOI 10.1126/science.1192912
Open Access Status Not yet assessed
Volume 330
Issue 6003
Start page 517
End page 521
Total pages 5
Place of publication Washington, D.C., United States
Publisher American Association for the Advancement of Science
Language eng
Subject 1000 General
Abstract The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.
Formatted abstract
The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide–cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.
Keyword Telangiectasia gene-product
Ataxia-telangiectasia
Dna-damage
Deficient mice
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID CA132813
569591
007784
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2011 Collection
School of Medicine Publications
 
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Created: Sun, 07 Nov 2010, 10:01:57 EST