FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage

Young Min Chung; See Hyoung Park; Wen Bin Tsai; Shih Ya Wang; Masa Aki Ikeda; Jonathan S. Berek; David J. Chen; Mickey C T Hu

doi:10.1038/ncomms2008

FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage

Young Min Chung, See Hyoung Park, Wen Bin Tsai, Shih Ya Wang, Masa Aki Ikeda, Jonathan S. Berek, David J. Chen, Mickey C T Hu

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64 Scopus citations

Abstract

DNA damage as a result of environmental stress is recognized by sensor proteins that trigger repair mechanisms, or, if repair is unsuccessful, initiate apoptosis. Defects in DNA damage-induced apoptosis promote genomic instability and tumourigenesis. The protein ataxia-telangiectasia mutated (ATM) is activated by DNA double-strand breaks and regulates apoptosis via p53. Here we show that FOXO3 interacts with the ATMĝ€"Chk2ĝ€"p53 complex, augments phosphorylation of the complex and induces the formation of nuclear foci in cells on DNA damage. FOXO3 is essential for DNA damage-induced apoptosis and conversely FOXO3 requires ATM, Chk2 and phosphorylated p53 isoforms to trigger apoptosis as a result of DNA damage. Under these conditions FOXO3 may also have a role in regulating chromatin retention of phosphorylated p53. These results suggest an essential link between FOXO3 and the ATMg53-mediated apoptotic programme following DNA damage.

Original language	English (US)
Article number	1000
Journal	Nature communications
Volume	3
DOIs	https://doi.org/10.1038/ncomms2008
State	Published - 2012

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms2008

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title = "FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage",

abstract = "DNA damage as a result of environmental stress is recognized by sensor proteins that trigger repair mechanisms, or, if repair is unsuccessful, initiate apoptosis. Defects in DNA damage-induced apoptosis promote genomic instability and tumourigenesis. The protein ataxia-telangiectasia mutated (ATM) is activated by DNA double-strand breaks and regulates apoptosis via p53. Here we show that FOXO3 interacts with the ATMĝ€{"}Chk2ĝ€{"}p53 complex, augments phosphorylation of the complex and induces the formation of nuclear foci in cells on DNA damage. FOXO3 is essential for DNA damage-induced apoptosis and conversely FOXO3 requires ATM, Chk2 and phosphorylated p53 isoforms to trigger apoptosis as a result of DNA damage. Under these conditions FOXO3 may also have a role in regulating chromatin retention of phosphorylated p53. These results suggest an essential link between FOXO3 and the ATMg53-mediated apoptotic programme following DNA damage.",

author = "Chung, {Young Min} and Park, {See Hyoung} and Tsai, {Wen Bin} and Wang, {Shih Ya} and Ikeda, {Masa Aki} and Berek, {Jonathan S.} and Chen, {David J.} and Hu, {Mickey C T}",

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AU - Chung, Young Min

AU - Park, See Hyoung

AU - Tsai, Wen Bin

AU - Wang, Shih Ya

AU - Ikeda, Masa Aki

AU - Berek, Jonathan S.

AU - Chen, David J.

AU - Hu, Mickey C T

PY - 2012

Y1 - 2012

N2 - DNA damage as a result of environmental stress is recognized by sensor proteins that trigger repair mechanisms, or, if repair is unsuccessful, initiate apoptosis. Defects in DNA damage-induced apoptosis promote genomic instability and tumourigenesis. The protein ataxia-telangiectasia mutated (ATM) is activated by DNA double-strand breaks and regulates apoptosis via p53. Here we show that FOXO3 interacts with the ATMĝ€"Chk2ĝ€"p53 complex, augments phosphorylation of the complex and induces the formation of nuclear foci in cells on DNA damage. FOXO3 is essential for DNA damage-induced apoptosis and conversely FOXO3 requires ATM, Chk2 and phosphorylated p53 isoforms to trigger apoptosis as a result of DNA damage. Under these conditions FOXO3 may also have a role in regulating chromatin retention of phosphorylated p53. These results suggest an essential link between FOXO3 and the ATMg53-mediated apoptotic programme following DNA damage.

AB - DNA damage as a result of environmental stress is recognized by sensor proteins that trigger repair mechanisms, or, if repair is unsuccessful, initiate apoptosis. Defects in DNA damage-induced apoptosis promote genomic instability and tumourigenesis. The protein ataxia-telangiectasia mutated (ATM) is activated by DNA double-strand breaks and regulates apoptosis via p53. Here we show that FOXO3 interacts with the ATMĝ€"Chk2ĝ€"p53 complex, augments phosphorylation of the complex and induces the formation of nuclear foci in cells on DNA damage. FOXO3 is essential for DNA damage-induced apoptosis and conversely FOXO3 requires ATM, Chk2 and phosphorylated p53 isoforms to trigger apoptosis as a result of DNA damage. Under these conditions FOXO3 may also have a role in regulating chromatin retention of phosphorylated p53. These results suggest an essential link between FOXO3 and the ATMg53-mediated apoptotic programme following DNA damage.

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FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage

Abstract

ASJC Scopus subject areas

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