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.
Highlights
The heat shock factor (HSF)1 activation is critical for maintaining homeostasis of the proteomes of cells and is mediated in large part by increased expression of classical heat shock proteins (HSP) such as HSP27, HSP70, and HSP90 [1]
Since our HSF1 binding partners screening assay revealed that Ku70 and Ku86 were the binding partners for HSF1, we examined damage responses after ionizing radiation (IR) in cells with or without HSF1
Since the regulation of the major HSPs does not explain the entire range of HSF1 functions, there are questions remaining regarding an alternative mechanism for how HSF1 may be involved in cancer initiation or progression
Summary
The heat shock factor (HSF) activation is critical for maintaining homeostasis of the proteomes of cells and is mediated in large part by increased expression of classical heat shock proteins (HSP) such as HSP27, HSP70, and HSP90 [1]. The HSF1-mediated stress response and the activity of specific HSPs have both been implicated in protecting organisms from a broad range of pathophysiological conditions, including thermal injury, ischemia/reperfusion, and chemotherapeutic agents/ ionizing radiation (IR) [2,3,4]. The effect of HSF1 activation goes far beyond these chaperones. It helps coordinate a range of fundamental cellular processes that are important to the fitness of malignant cells, including cell cycle control, ribosome biogenesis, protein translation, and glucose metabolism [6, 7]
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