CEA, Institute of Molecular and Cellular Radiobiology, 18 route du Panorama, Fontenay aux Roses, F-92265, France.
DNA Repair (Amst). 2013 Mar 1;12(3):227-37. doi: 10.1016/j.dnarep.2012.12.006. Epub 2013 Jan 15.
Inhibition of DNA repair has been proposed as a mechanism underlying heat-induced sensitization of tumour cells to some anticancer treatments. Base excision repair (BER) constitutes the main pathway for the repair of DNA lesions induced by oxidizing or alkylating agents. Here, we report that mild hyperthermia, without toxic consequences per se, affects cellular DNA glycosylase activities, thus impairing BER. Exposure of cells to mild hyperthermia leads to a rapid and selective inactivation of OGG1 (8-oxoguanine DNA glycosylase) associated with the relocalisation of the protein into a detergent-resistant cellular fraction. Following its inactivation, OGG1 is ubiquitinated and directed to proteasome-mediated degradation, through a CHIP (C-terminus of HSC70-interacting protein) E3 ligase-mediated process. Moreover, the residual OGG1 accumulates in the perinuclear region leading to further depletion from the nucleus. As a consequence, HeLa cells subjected to hyperthermia and exposed to a genotoxic treatment have a reduced capacity to repair OGG1 cognate base lesions and an enhanced cell growth defect. The partial alleviation of this response by OGG1 overexpression indicates that heat-induced glycosylase inactivation contributes to the synergistic effect of hyperthermia on genotoxic treatments. Taken together, our results suggest that OGG1 inhibition contributes to heat-induced chemosensitisation of cells and could lay the basis for new anticancer therapeutic protocols that include hyperthermia.
抑制 DNA 修复已被提议作为热诱导肿瘤细胞对某些抗癌治疗敏感的机制。碱基切除修复 (BER) 是修复氧化或烷化剂诱导的 DNA 损伤的主要途径。在这里，我们报告说，轻度热疗本身没有毒性后果，会影响细胞的 DNA 糖苷酶活性，从而损害 BER。细胞暴露于轻度热疗会导致 OGG1（8-氧鸟嘌呤 DNA 糖苷酶）的快速和选择性失活，与蛋白质重新定位到去污剂抗性细胞部分有关。OGG1 失活后，通过 CHIP（HSC70 相互作用蛋白 C 端）E3 连接酶介导的过程被泛素化并定向到蛋白酶体介导的降解。此外，残留的 OGG1 积累在核周区域，导致核内进一步耗竭。因此，暴露于热疗和遗传毒性处理的 HeLa 细胞修复 OGG1 同源碱基损伤的能力降低，细胞生长缺陷增强。通过 OGG1 过表达部分缓解这种反应表明，热诱导的糖苷酶失活有助于热疗对遗传毒性处理的协同作用。总之，我们的研究结果表明，OGG1 抑制有助于细胞的热诱导化疗增敏，并且可以为包括热疗在内的新型抗癌治疗方案奠定基础。
