ATM (ataxia-telangiectasia mutated), ATR (ATM- and Rad3-related) and DNA-PK (DNA-dependent protein kinase), important regulators of genome stability, belong to the PIKK (phosphoinositide 3-kinase-like kinase) family of protein kinases. In the present study, DNA-affinity chromatography was used to identify DNA-binding proteins phosphorylated by these kinases. This resulted in the identification of FUS (fused in sarcoma)/TLS (translocated in liposarcoma) as an in vitro target of the PIKKs. FUS is a member of the Ewing's sarcoma family of proteins that appears to play a role in regulating genome stability, since mice lacking FUS show chromosomal instability and defects in meiosis. The residues in FUS that are phosphorylated in vitro and in vivo were identified, and phospho-specific antibodies were generated to demonstrate that FUS becomes phosphorylated at Ser42in vivo, primarily in response to agents that cause DSBs (double-strand breaks). DSB-induced FUS phosphorylation in vivo at Ser42 requires ATM and not DNA-PK. Although Ser42 is retained in the oncogenic FUS–CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein 10] fusion generated by a t(12;16)(q13;p11) chromosomal translocation, Ser42 in FUS–CHOP is not phosphorylated after DNA damage. These results identify FUS as a new target of the ATM-signalling pathway and strengthen the notion that FUS regulates genome stability.
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October 2008
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Research Article|
September 25 2008
Identification and characterization of FUS/TLS as a new target of ATM
Mary Gardiner;
Mary Gardiner
1MRC Protein Phosphorylation Unit, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, U.K.
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Rachel Toth;
Rachel Toth
1MRC Protein Phosphorylation Unit, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, U.K.
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Franck Vandermoere;
Franck Vandermoere
1MRC Protein Phosphorylation Unit, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, U.K.
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Nicholas A. Morrice;
Nicholas A. Morrice
1MRC Protein Phosphorylation Unit, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, U.K.
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John Rouse
John Rouse
1
1MRC Protein Phosphorylation Unit, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, U.K.
1To whom correspondence should be addressed (email j.rouse@dundee.ac.uk).
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Publisher: Portland Press Ltd
Received:
June 04 2008
Revision Received:
June 30 2008
Accepted:
July 11 2008
Accepted Manuscript online:
July 11 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 415 (2): 297–307.
Article history
Received:
June 04 2008
Revision Received:
June 30 2008
Accepted:
July 11 2008
Accepted Manuscript online:
July 11 2008
Citation
Mary Gardiner, Rachel Toth, Franck Vandermoere, Nicholas A. Morrice, John Rouse; Identification and characterization of FUS/TLS as a new target of ATM. Biochem J 15 October 2008; 415 (2): 297–307. doi: https://doi.org/10.1042/BJ20081135
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