Human PTIP facilitates ATM-mediated activation of p53 and promotes cellular resistance to ionizing radiation
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- Dr Paul Jowsey
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| Author(s) | | Jowsey PA, Doherty AJ, Rouse J |
| Publication type | | Article |
| Journal | | Journal of Biological Chemistry |
| Year | | 2004 |
| Volume | | 279 |
| Issue | | 53 |
| Pages | | 55562-55569 |
| ISSN (print) | | 0021-9258 |
| ISSN (electronic) | | 1083-351X |
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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. |
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| Publisher | | American Society for Biochemistry and Molecular Biology, Inc. |
| URL | | http://dx.doi.org/10.1074/jbc.M411021200 |
| DOI | | 10.1074/jbc.M411021200 |
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