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hPTIP facilitates ATM-mediated activation of p53 and promotes cellular resistance to ionising radiation

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

Abstract

Mus musculus Ptip is an essential gene required for maintenance of genome stability although it's 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/ATR 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 ionising 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 characterising the cellular roles of hPTIP are also presented. siRNA was used to show that hPTIP is required for ATM-mediated phosphorylation of p53 at Ser15 and for IR-induced upregulation of the CDK inhibitor p21. Lowering hPTIP levels also resulted in increased cellular sensitivity to IR suggesting that this protein plays a critical role in maintaining genome stability

Publisher: American Society for Biochemistry and Molecular Biology
Year: 2004
OAI identifier: oai:sro.sussex.ac.uk:981
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