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

  1. Lookup NU author(s)
  2. Dr Paul Jowsey
Author(s)Jowsey PA, Doherty AJ, Rouse J
Publication type Article
JournalJournal of Biological Chemistry
Year2004
Volume279
Issue53
Pages55562-55569
ISSN (print)0021-9258
ISSN (electronic)1083-351X
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
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.
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc.
URLhttp://dx.doi.org/10.1074/jbc.M411021200
DOI10.1074/jbc.M411021200
Actions    Link to this publication