Human PTIP facilitates ATM-mediated activation of p53 and promotes cellular resistance to ionizing radiation

Paul A. Jowsey, Aidan J. Doherty, John Rouse

    Research output: Contribution to journalArticle

    56 Citations (Scopus)

    Abstract

    Mus musculusPax2 transactivation domain-interacting protein (Ptip) is an essential gene required for the maintenance of genome stability, although its precise molecular role is unclear. Human PTIP (hPTIP) was recently isolated in a screen for proteins, translated from cDNA pools, capable of interacting with peptides phosphorylated by the ATM (ataxia telangiectasia-mutated)/ATR (ataxia telangiectasia-related) protein kinases. hPTIP was described as a 757-amino acid protein bearing four BRCT domains. Here we report that instead full-length endogenous hPTIP contains 1069 amino acids and six BRCT domains. hPTIP shows increased association with 53BP1 in response to ionizing radiation (IR) but not in response to other DNA-damaging agents. Whereas translocation of both 53BP1 and hPTIP to sites of IR-induced DNA damage occurs independently of ATM, IR-induced association of PTIP and 53BP1 requires ATM. Deletion analysis identified the domains of 53BP1 and hPTIP required for protein-protein interaction and focus formation. Data characterizing the cellular roles of hPTIP are also presented. Small interfering RNA was used to show that hPTIP is required for ATM-mediated phosphorylation of p53 at Ser15 and for IR-induced up-regulation of the cyclin-dependent kinase inhibitor p21. Lowering hPTIP levels also increased cellular sensitivity to IR, suggesting that this protein plays a critical role in maintaining genome stability.
    Original languageEnglish
    Pages (from-to)55562-55569
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume279
    Issue number53
    DOIs
    Publication statusPublished - 2004

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    Ataxia Telangiectasia
    Ionizing radiation
    Ionizing Radiation
    Chemical activation
    Proteins
    Genes
    Genomic Instability
    Bearings (structural)
    Association reactions
    Cyclin-Dependent Kinase Inhibitor p21
    Amino Acids
    Phosphorylation
    DNA
    Protein Kinases
    Small Interfering RNA
    Essential Genes
    Complementary DNA
    Transcriptional Activation
    DNA Damage
    Peptides

    Cite this

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    title = "Human PTIP facilitates ATM-mediated activation of p53 and promotes cellular resistance to ionizing radiation",
    abstract = "Mus musculusPax2 transactivation domain-interacting protein (Ptip) is an essential gene required for the maintenance of genome stability, although its precise molecular role is unclear. Human PTIP (hPTIP) was recently isolated in a screen for proteins, translated from cDNA pools, capable of interacting with peptides phosphorylated by the ATM (ataxia telangiectasia-mutated)/ATR (ataxia telangiectasia-related) protein kinases. hPTIP was described as a 757-amino acid protein bearing four BRCT domains. Here we report that instead full-length endogenous hPTIP contains 1069 amino acids and six BRCT domains. hPTIP shows increased association with 53BP1 in response to ionizing radiation (IR) but not in response to other DNA-damaging agents. Whereas translocation of both 53BP1 and hPTIP to sites of IR-induced DNA damage occurs independently of ATM, IR-induced association of PTIP and 53BP1 requires ATM. Deletion analysis identified the domains of 53BP1 and hPTIP required for protein-protein interaction and focus formation. Data characterizing the cellular roles of hPTIP are also presented. Small interfering RNA was used to show that hPTIP is required for ATM-mediated phosphorylation of p53 at Ser15 and for IR-induced up-regulation of the cyclin-dependent kinase inhibitor p21. Lowering hPTIP levels also increased cellular sensitivity to IR, suggesting that this protein plays a critical role in maintaining genome stability.",
    author = "Jowsey, {Paul A.} and Doherty, {Aidan J.} and John Rouse",
    note = "dc.publisher: American Society for Biochemistry and Molecular Biology dc.description.sponsorship: This work was supported by the Medical Research Council UK (to P. A. J. and J. R.) and the Association for International Cancer Research and the Royal Society (to A. J. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.",
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    language = "English",
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    Human PTIP facilitates ATM-mediated activation of p53 and promotes cellular resistance to ionizing radiation. / Jowsey, Paul A.; Doherty, Aidan J.; Rouse, John.

    In: Journal of Biological Chemistry, Vol. 279, No. 53, 2004, p. 55562-55569.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Human PTIP facilitates ATM-mediated activation of p53 and promotes cellular resistance to ionizing radiation

    AU - Jowsey, Paul A.

    AU - Doherty, Aidan J.

    AU - Rouse, John

    N1 - dc.publisher: American Society for Biochemistry and Molecular Biology dc.description.sponsorship: This work was supported by the Medical Research Council UK (to P. A. J. and J. R.) and the Association for International Cancer Research and the Royal Society (to A. J. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    PY - 2004

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    N2 - Mus musculusPax2 transactivation domain-interacting protein (Ptip) is an essential gene required for the maintenance of genome stability, although its precise molecular role is unclear. Human PTIP (hPTIP) was recently isolated in a screen for proteins, translated from cDNA pools, capable of interacting with peptides phosphorylated by the ATM (ataxia telangiectasia-mutated)/ATR (ataxia telangiectasia-related) protein kinases. hPTIP was described as a 757-amino acid protein bearing four BRCT domains. Here we report that instead full-length endogenous hPTIP contains 1069 amino acids and six BRCT domains. hPTIP shows increased association with 53BP1 in response to ionizing radiation (IR) but not in response to other DNA-damaging agents. Whereas translocation of both 53BP1 and hPTIP to sites of IR-induced DNA damage occurs independently of ATM, IR-induced association of PTIP and 53BP1 requires ATM. Deletion analysis identified the domains of 53BP1 and hPTIP required for protein-protein interaction and focus formation. Data characterizing the cellular roles of hPTIP are also presented. Small interfering RNA was used to show that hPTIP is required for ATM-mediated phosphorylation of p53 at Ser15 and for IR-induced up-regulation of the cyclin-dependent kinase inhibitor p21. Lowering hPTIP levels also increased cellular sensitivity to IR, suggesting that this protein plays a critical role in maintaining genome stability.

    AB - Mus musculusPax2 transactivation domain-interacting protein (Ptip) is an essential gene required for the maintenance of genome stability, although its precise molecular role is unclear. Human PTIP (hPTIP) was recently isolated in a screen for proteins, translated from cDNA pools, capable of interacting with peptides phosphorylated by the ATM (ataxia telangiectasia-mutated)/ATR (ataxia telangiectasia-related) protein kinases. hPTIP was described as a 757-amino acid protein bearing four BRCT domains. Here we report that instead full-length endogenous hPTIP contains 1069 amino acids and six BRCT domains. hPTIP shows increased association with 53BP1 in response to ionizing radiation (IR) but not in response to other DNA-damaging agents. Whereas translocation of both 53BP1 and hPTIP to sites of IR-induced DNA damage occurs independently of ATM, IR-induced association of PTIP and 53BP1 requires ATM. Deletion analysis identified the domains of 53BP1 and hPTIP required for protein-protein interaction and focus formation. Data characterizing the cellular roles of hPTIP are also presented. Small interfering RNA was used to show that hPTIP is required for ATM-mediated phosphorylation of p53 at Ser15 and for IR-induced up-regulation of the cyclin-dependent kinase inhibitor p21. Lowering hPTIP levels also increased cellular sensitivity to IR, suggesting that this protein plays a critical role in maintaining genome stability.

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    JO - Journal of Biological Chemistry

    JF - Journal of Biological Chemistry

    SN - 0021-9258

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    ER -