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

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.
Mesh Terms:
Amino Acid Sequence, Blotting, Western, Carrier Proteins, Cell Cycle Proteins, Cell Line, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, DNA Damage, DNA, Complementary, DNA-Binding Proteins, Dose-Response Relationship, Drug, Dose-Response Relationship, Radiation, Gene Deletion, Genome, Hela Cells, Humans, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Microscopy, Fluorescence, Molecular Sequence Data, Nuclear Proteins, Phosphoproteins, Phosphorylation, Plasmids, Protein Structure, Tertiary, Protein Transport, Protein-Serine-Threonine Kinases, RNA Interference, Radiation Tolerance, Radiation, Ionizing, Sequence Homology, Amino Acid, Serine, Time Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Up-Regulation
J. Biol. Chem.
Date: Dec. 31, 2004
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