title: Ionizing radiation enhances double-strand-break repair in rapamycin-treated ataxia telangiectasia lymphoblasts.
abstract: OBJECTIVE
  Unlike normal cells, ataxia telangiectasia (A-T) cells do not exhibit enhanced double-strand-break (dsb)-repair fidelity after ionizing radiation (IR) exposure. DNA-repair induction and other responses to IR are mediated by signalling pathways that are defective in A-T cells. Ataxia telangiectasia mutated (ATM) protein, the mutated protein in A-T cells, is homologous to members of the P13-kinase, including the rapamycin target FRAP. Rapamycin kills normal cells more readily in normal than in A-T cells, and inhibits the FRAP target p70 S6 kinase (p70S6K) more readily in normal than in A-T cells. Also, PHAS-1, another FRAP target, may also be a substrate for ATM. Because ATM plays a role in the response of mammalian cells to rapamycin, the effect of rapamycin on IR enhancement of dsb repair was investigated.
  
  
  METHODS
  Double-strand-break repair by normal and A-T lymphoblasts, either untreated or treated with rapamycin and y-irradiated, was analysed using shuttle pZ189 containing a dsb.
  
  
  RESULTS
  Double-strand-break-rejoining fidelity in linear plasmids (linDNA) processed in either untreated or rapamycin-treated normal cells increased about twofold if transfection occurred immediately after host irradiation. In contrast, radiation did not increase or decrease the repair fidelity by untreated A-T host cells. But, like normal hosts, dsb-repair fidelity improved twofold in A-T hosts treated with rapamycin. Treatment with the P13-kinase inhibitor LY294002 did not alter dsb-rejoining fidelity in normal or in A-T hosts.
  
  
  CONCLUSIONS
  These findings demonstrate that rapamycin does not affect IR enhancement of dsb-repair fidelity in normal cells but restores this phenomenon in A-T lymphoblasts, and suggests the involvement of a rapamycin-sensitive pathway in radiation-enhanced dsb repair.
authors.affiliation: Department of Oral Diagnosis, School of Dental Medicine, University of Connecticut Health Center, Farmington 06030-1605, USA. sikpi@nso2.uchc.edu
authors.forename: M O
authors.initials: MO
authors.lastname: Sikpi
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
mesh_terms: D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D004260:DNA Repair; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000528:radiation effects; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D002867:Chromones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004247:DNA; D020123:Sirolimus