2007 Fiscal Year Final Research Report Summary
To clarify of the mechanism of thermotolerance
| Project/Area Number |
18390335
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Radiation science
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| Research Institution | Nara Medical University |
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Principal Investigator |
TAKAHASHI Akihisa Nara Medical University, Department of Biology, Shool of Medicine, Assistant Professor (60275336)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Radiation Oncology / Hyperthermia / Thermotolerance / DNA Double Strand Break |
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| Research Abstract |
Although heat shock proteins (HSPs) are well known to contribute to thermotolerance, they only play a supporting role in the phenomenon. Recently, it has been reported that heat sensitivity depends on heat-induced DNA double-strand breaks (DSBs), and thermotolerance also depends on the suppression of DSB formation. However the critical elements involved in thermotolerance have not yet been fully identified. Heat produces DSBs and leads to cell death through denaturation and dysfunction of heat-labile repair proteins such as DNA polymerase β (Polβ). Here we show that thermotolerance was partially suppressed in Polβ-/- mouse embryonic fibroblasts (MEFs) when compared to the wild type MEFs, and was also suppressed in the presence of the HSP inhibitor, KNK437, in both cell lines. Moreover, we found that heat-induced γH2AX was suppressed in the thermotolerant cells. These results suggest that Polβ at least contributes to thermotolerance through its reactivation and stimulation by Hsp27 and Hsp70. In addition, it appears possible that fewer DSBs were formed after a challenging heat exposure because pre-heat-induced Hsp27 and Hsp70 can rescue or restore other, as yet unidentified, heat-labile proteins besides Polβ. Our novel findings provide strong evidence that Polβ functions as a critical element involved in thermotolerance and exerts an important role in heat-induced DSBs.
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