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

Jowsey, Paul A., Doherty, Aidan J. and Rouse, John (2004) Human PTIP facilitates ATM-mediated activation of p53 and promotes cellular resistance to ionizing radiation. Journal of Biological Chemistry, 279 (53). pp. 55562-9. ISSN 0021-9258

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Mus musculus Pax2 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 Ser(15) 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.

Item Type: Article
Keywords: Amino Acid Sequence Blotting, Western Carrier Proteins/chemistry/ physiology Cell Cycle Proteins/metabolism Cell Line Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p21 DNA Damage DNA, Complementary/metabolism DNA-Binding Proteins Dose-Response Relationship, Drug Dose-Response Relationship, Radiation Gene Deletion Genome Hela Cells Humans Immunoprecipitation Intracellular Signaling Peptides and Proteins/metabolism Microscopy, Fluorescence Molecular Sequence Data Nuclear Proteins/chemistry/ physiology Phosphoproteins/metabolism Phosphorylation Plasmids/metabolism Protein Structure, Tertiary Protein Transport Protein-Serine-Threonine Kinases/ metabolism RNA Interference Radiation Tolerance Radiation, Ionizing Research Support, Non-U.S. Gov't Sequence Homology, Amino Acid Serine/chemistry Time Factors Tumor Suppressor Protein p53/ metabolism Tumor Suppressor Proteins Up-Regulation
Depositing User: Aidan Doherty
Date Deposited: 27 Nov 2006
Last Modified: 30 Nov 2012 16:50
Google Scholar:41 Citations
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