{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T16:29:48Z","timestamp":1759336188621},"reference-count":66,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2003,5,19]],"date-time":"2003-05-19T00:00:00Z","timestamp":1053302400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2003,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A synergistic increase in cell killing is observed when a heat\u2010shock is administered prior to, during, or immediately after exposure to ionizing radiation (IR). This phenomenon, known as heat\u2010radiosensitization, is believed to be mediated by inhibition of repair of radiation\u2010induced double strand breaks (DSB) when cells are exposed to temperatures above 42\u00b0C. However, the mechanism by which heat inhibits DSB repair is unclear. The bulk of radiation\u2010induced DSBs are repaired via the non\u2010homologous end\u2010joining pathway (NHEJ). Several reports indicate that the Ku70 and Ku80 subunits of the mammalian DNA\u2010dependent protein kinase (DNA\u2010PK), a complex involved in NHEJ, appear to be susceptible to a heat\u2010induced loss of DNA\u2010binding activity, with Ku80 representing the heat\u2010sensitive component. Since the heat\u2010induced loss and subsequent recovery of Ku\u2013DNA binding activity correlates well with heat\u2010radiosensitization, a role for Ku80 and NHEJ in heat\u2010radiosensitization has been proposed. However, direct evidence implicating Ku80 (and NHEJ) in heat\u2010radiosensitization has been indeterminate. In this study, we demonstrate that equitoxic heat treatments at 42.5\u201345.5\u00b0C induce a similar amount of aggregation of Ku80 in human U\u20101 melanoma cells. These data suggest that the time\u2013temperature\u2010dependent relationship between heat lethality and Ku80 aggregation are similar. However, the aggregation\/disaggregation of Ku80 and its transient or permanent inactivation is unrelated to heat\u2010radiosensitization. When survival curves were obtained for irradiated or irradiated and heated Ku80<jats:sup>\u2212\/\u2212<\/jats:sup> mouse embryo fibroblasts (MEFs) and compared with survival curves obtained for wild\u2010type (WT) cells, we found that heat\u2010radiosensitization was not reduced in the Ku80<jats:sup>\u2212\/\u2212<\/jats:sup> cells, but actually increased. Thus, our findings indicate that Ku80 is not essential for heat\u2010radiosensitization. Non\u2010involvement of Ku\u2010dependent or Ku\u2010independent NHEJ pathways in heat\u2010radiosensitization was confirmed by comparing clonogenic survival between DNA ligase IV\u2010defective and WT human cells. Our data therefore implicate homologous recombination in inhibition of repair of radiation\u2010induced DSBs and as a target for heat\u2010radiosensitization. J. Cell. Physiol. 196: 557\u2013564, 2003. \u00a9 2003 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcp.10334","type":"journal-article","created":{"date-parts":[[2003,7,28]],"date-time":"2003-07-28T11:14:17Z","timestamp":1059390857000},"page":"557-564","source":"Crossref","is-referenced-by-count":16,"title":["The non\u2010homologous end\u2010joining pathway is not involved in the radiosensitization of mammalian cells by heat shock"],"prefix":"10.1002","volume":"196","author":[{"given":"Joseph R.","family":"Dynlacht","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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