The Cancer Research UK/Medical Research Council Gray Institute for Radiation Oncology and Biology, University of Oxford, Churchill Hospital, Oxford OX3 7DQ, United Kingdom.
Cancer Res. 2010 Feb 1;70(3):925-35. doi: 10.1158/0008-5472.CAN-09-2715. Epub 2010 Jan 26.
Questions exist concerning the effects of acute versus chronic hypoxic conditions on DNA replication and genomic stability that may influence tumorigenesis. Severe hypoxia causes replication arrest independent of S-phase checkpoint, DNA damage response, or transformation status. Arrests occur during both the initiation and elongation phases of DNA replication, correlated with a rapid decrease in available deoxynucleotide triphosphates. With fluctuating oxygen tensions in tumors, arrested hypoxic cells may undergo rapid reperfusion and reoxygenation that leads to reoxygenation-induced DNA damage. In cells subjected to chronic hypoxia, we found that replicative restart was inhibited along with numerous replication factors, including MCM6 and RPA, the latter of which limits the hypoxia-induced DNA damage response. In contrast, in cells where replicative restart occurred, it was accompanied by extensive reoxygenation-induced DNA damage and compromised DNA repair. We found that cells reoxygenated after acute hypoxia underwent rapid p53-dependent apoptosis. Our findings suggest that cells lacking functional p53 are more susceptible to genomic instability and potentially tumorigenesis if they experience reoxygenation after acute exposure to hypoxia.
关于急性与慢性缺氧条件对 DNA 复制和基因组稳定性的影响存在疑问，这些影响可能会影响肿瘤的发生。严重的缺氧会导致复制停滞，而与 S 期检查点、DNA 损伤反应或转化状态无关。停滞发生在 DNA 复制的起始和延伸阶段，与可用的脱氧核苷酸三磷酸迅速减少相关。由于肿瘤中氧气张力的波动，被阻断的缺氧细胞可能会迅速再灌注和再氧化，导致再氧化诱导的 DNA 损伤。在慢性缺氧的细胞中，我们发现复制起始受到抑制，伴随着许多复制因子，包括 MCM6 和 RPA，后者限制了缺氧诱导的 DNA 损伤反应。相比之下，在复制起始发生的细胞中，伴随着广泛的再氧化诱导的 DNA 损伤和 DNA 修复受损。我们发现，急性缺氧后再氧化的细胞经历了快速的 p53 依赖性细胞凋亡。我们的研究结果表明，如果细胞在急性缺氧暴露后经历再氧化，缺乏功能 p53 的细胞更容易发生基因组不稳定性，并且可能发生肿瘤形成。
