Identification and characterization of FUS/TLS as a new target of ATM

Mary Gardiner, Rachel Toth, Franck Vandermoere, Nicholas A. Morrice, John Rouse

    Research output: Contribution to journalArticle

    55 Citations (Scopus)

    Abstract

    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 Ser(42) in vivo, primarily in response to agents that clause DSBs (double-strand breaks). DSB-induced FUS phosphorylation in vivo at Ser(42) requires ATM and not DNA-PK. Although Set(42) 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, Ser(42) 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.

    Original languageEnglish
    Pages (from-to)297-307
    Number of pages11
    JournalBiochemical Journal
    Volume415
    DOIs
    Publication statusPublished - 15 Oct 2008

    Cite this

    Gardiner, Mary ; Toth, Rachel ; Vandermoere, Franck ; Morrice, Nicholas A. ; Rouse, John. / Identification and characterization of FUS/TLS as a new target of ATM. In: Biochemical Journal. 2008 ; Vol. 415. pp. 297-307.
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    abstract = "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 Ser(42) in vivo, primarily in response to agents that clause DSBs (double-strand breaks). DSB-induced FUS phosphorylation in vivo at Ser(42) requires ATM and not DNA-PK. Although Set(42) 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, Ser(42) 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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    Identification and characterization of FUS/TLS as a new target of ATM. / Gardiner, Mary; Toth, Rachel; Vandermoere, Franck; Morrice, Nicholas A.; Rouse, John.

    In: Biochemical Journal, Vol. 415, 15.10.2008, p. 297-307.

    Research output: Contribution to journalArticle

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