Development of thermotolerance requires interaction between polymerase-beta and heat shock proteins.
Although heat shock proteins (HSP) 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 (DSB), and that thermotolerance also depends on the suppression of DSB formation. However the critical elements involved in thermotolerance have not yet been fully identified. Heat produces DSB and leads to cell death through denaturation and dysfunction of heat-labile repair proteins such as DNA polymerase-beta (Pol beta). Here the authors show that thermotolerance was partially suppressed in Pol beta(-/-) mouse embryonic fibroblasts (MEF) when compared to the wild-type MEF, and was also suppressed in the presence of the HSP inhibitor, KNK437, in both cell lines. Moreover, the authors found that heat-induced gamma H2AX was suppressed in the thermotolerant cells. These results suggest that Pol beta at least contributes to thermotolerance through its reactivation and stimulation by Hsp27 and Hsp70. In addition, it appears possible that fewer DSB were formed after a challenging heat exposure because preheat-induced Hsp27 and Hsp70 can rescue or restore other, as yet unidentified, heat-labile proteins besides Pol beta. The present novel findings provide strong evidence that Pol beta functions as a critical element involved in thermotolerance and exerts an important role in heat-induced DSB.
Takahashi
Akihisa
A
Department of Biology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
Yamakawa
Nobuhiro
N
Mori
Eiichiro
E
Ohnishi
Ken
K
Yokota
Shin-ichi
S
Sugo
Noriyuki
N
Aratani
Yasuaki
Y
Koyama
Hideki
H
Ohnishi
Takeo
T
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D019951:DNA Polymerase beta / Q000378:metabolism*; D005334:Fever / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D011760:Pyrrolidinones / Q000494:pharmacology
D001559:Benzhydryl Compounds; D006360:Heat-Shock Proteins; C410027:KNK 437; D011760:Pyrrolidinones; D019951:DNA Polymerase beta