Heat shock factor 1, an inhibitor of non-homologous end joining repair
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Ga-Young Kang1, Eun-Ho Kim2, Hae-June Lee2, Na-Yeon Gil3, Hyuk-Jin Cha3, Yun-Sil Lee1
1Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120–750, Korea
2Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139–706, Korea
3College of Natural Sciences, Department of Life Sciences, Sogang University, Seoul 121–742, Korea
Yun-Sil Lee, e-mail: email@example.com
Keywords: HSF1, Ku70, Ku86, NHEJ Repair, cellular carcinogenesis
Received: June 02, 2015 Accepted: August 13, 2015 Published: August 24, 2015
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.
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