Hyperthermia inhibits homologous recombination repair and sensitizes cells to ionizing radiation in a time- and temperature-dependent manner
Hyperthermia inhibits homologous recombination repair and sensitizes cells to ionizing radiation in a time- and temperature-dependent manner
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DOI：
10.1002/jcp.24302
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发表时间：
2013-07-01
影响因子：
5.6
通讯作者：
Kato, Takamitsu A.
中科院分区：
文献类型：
--
作者：
Genet, Stefan C.;Fujii, Yoshihiro;Kato, Takamitsu A.
热疗长期以来一直被认为是一种具有抗肿瘤作用的放射增敏剂，并已发展成为一种治疗应用。高热诱导的放射致敏机制与DNA修复的抑制高度相关。我们的研究旨在通过一系列DNA修复缺陷的中国仓鼠细胞，揭示热疗如何在电离辐射致敏细胞过程中失活同源重组修复。观察到在42.5摄氏度和高于42.5摄氏度的热疗引起的细胞毒性的显著差异。在野生型和非同源末端连接修复突变体中，S期晚期细胞表现出比g1期细胞多一倍的热致辐射敏化效应。在g2期细胞中，辐射诱导的DNA双链断裂和高温暴露导致的染色质损伤大约是G0/G1期细胞的两倍。此外，g2期细胞修复DNA损伤所需的时间大约是G0/ g1期细胞的两倍。为了补充这些发现，在DNA双链断裂位点观察到辐射诱导的Rad51病灶形成，随着高温暴露的温度和时间逐渐解离。随着时间的推移，解离的Rad51蛋白在损伤部位重新形成病灶，其发生趋势也与高温暴露的温度和时间有关。这些发现表明Rad51在不同的高温条件下在DNA双链断裂位点的解离和随后的重组在高温诱导的放射致敏中起重要作用。j .细胞。中国生物医学工程学报，2013,31(2):473 - 481。(c) 2012 Wiley期刊有限公司
Hyperthermia has long been known as a radio-sensitizing agent that displays anti-tumor effects, and has been developed as a therapeutic application. The mechanisms of hyperthermia-induced radio-sensitization are highly associated with inhibition of DNA repair. Our investigations aimed to show how hyperthermia inactivate homologous recombination repair in the process of sensitizing cells to ionizing radiation by using a series of DNA repair deficient Chinese Hamster cells. Significant differences in cellular toxicity attributable to hyperthermia at and above 42.5 degrees C were observed. In wild-type and non-homologous end joining repair mutants, cells in late S phase showed double the amount heat-induced radio-sensitization effects of G1-phase cells. Both radiation-induced DNA double strand breaks and chromatin damage resulting from hyperthermia exposure was measured to be approximately two times higher in G2-phase cells than G0/G1 cells. Additionally, G2-phase cells took approximately two times as long to repair DNA damage over time than G0/G1-phase cells. To supplement these findings, radiation-induced Rad51 foci formations at DNA double strand break sites were observed to gradually dissociate in response to the temperature and time of hyperthermia exposure. Dissociated Rad51 proteins subsequently re-formed foci at damage sites with time, and occurred in a trend also related to temperature and time of hyperthermia exposure. These findings suggest Rad51's dissociation and subsequent reformation at DNA double strand break sites in response to varying hyperthermia conditions plays an important role in hyperthermia-induced radio-sensitization. J. Cell. Physiol. 228: 14731481, 2013. (c) 2012 Wiley Periodicals, Inc.