title: Heat shock factor 1, an inhibitor of non-homologous end joining repair.
abstract: A novel role for HSF1 as an inhibitor of non-homologous end joining (NHEJ) repair activity was identified. HSF1 interacted directly with both of the N-terminal sequences of the Ku70 and Ku86 proteins, which inhibited the endogenous heterodimeric interaction between Ku70 and Ku86. The blocking of the Ku70 and Ku86 interaction by HSF1 induced defective NHEJ repair activity and ultimately activated genomic instability after ionizing radiation (IR), which was similar to effects seen in Ku70 or Ku80 knockout cells. The binding activity between HSF1 and Ku70 or Ku86 was dependent on DNA damage response such as IR exposure, but not on the heat shock mediated transcriptional activation of HSF1. Moreover, the posttranslational modification such as phosphorylation, acetylation and sumoylation of HSF1 did not alter the binding activities of HSF1-Ku70 or HSF1-Ku86. Furthermore, the defect in DNA repair activity by HSF1 was observed regardless of p53 status. Rat mammary tumors derived using dimethylbenz(a)anthracence revealed that high levels of HSF1 expression which correlate with aggressive malignancy, interfered with the binding of Ku70-Ku80. This data suggests that HSF1 interacts with both Ku70 and Ku86 to induce defective NHEJ repair activity and genomic instability, which in turn suggests a novel mechanism of HSF1-mediated cellular carcinogenesis.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Ga-Young
authors.initials: GY
authors.lastname: Kang
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
authors.forename: Eun-Ho
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
authors.forename: Hae-June
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Natural Sciences, Department of Life Sciences, Sogang University, Seoul 121-742, Korea.
authors.forename: Na-Yeon
authors.initials: NY
authors.lastname: Gil
authors.affiliation: College of Natural Sciences, Department of Life Sciences, Sogang University, Seoul 121-742, Korea.
authors.forename: Hyuk-Jin
authors.initials: HJ
authors.lastname: Cha
authors.affiliation: Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004249:DNA Damage; D059766:DNA End-Joining Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D057809:HEK293 Cells; D000076249:Heat Shock Transcription Factors; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D000072200:Ku Autoantigen; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D011839:Radiation, Ionizing; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D014157:Transcription Factors; C000606512:Xrcc5 protein, mouse; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; C000606511:Xrcc6 protein, rat; D000072200:Ku Autoantigen
keywords: HSF1; Ku70; Ku86; NHEJ Repair; cellular carcinogenesis