Inhibition of ATR leads to increased sensitivity to hypoxia/reoxygenation
Inhibition of ATR leads to increased sensitivity to hypoxia/reoxygenation
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DOI：
10.1158/0008-5472.can-04-1520
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发表时间：
2004-09-15
期刊：
影响因子：
11.2
通讯作者：
Giaccia, AJ
中科院分区：
文献类型：
--
作者：
Hammond, EM;Dorie, MJ;Giaccia, AJ
肿瘤血管的短暂打开和关闭导致严重的缺氧（缺氧），然后再充氧。这对那些因氧气水平降低而失去对杀死的敏感性的细胞施加了积极的选择压力。这些细胞有效抵抗缺氧诱导的细胞凋亡和常规治疗方法。在这里，我们展示了缺氧诱导的s期阻滞在停滞复制分叉的单链DNA区域产生，并发出ATR激活的信号。s期细胞是细胞周期中对缺氧/再氧胁迫最敏感的阶段。当暴露于缺氧条件下再氧化时，ATR的丧失或ATR激酶活性的抑制会导致s期细胞进一步丧失生殖活力，但对DNA合成的抑制作用很小。这至少在一定程度上是通过Chk1信号介导的，因为Chk1的缺失也会导致对缺氧/再氧化的敏感性增加。观察到的生殖存活率的下降部分是由于缺氧暴露时，在没有充分的ATR活性的情况下，s期细胞中DNA损伤的积累。因此，ATR在缺氧暴露期间保护停滞的复制分叉。综上所述，ATR和Chk1在细胞对缺氧/再氧化的反应中起关键作用，ATR和Chk1的抑制剂代表了新的缺氧细胞毒素。
The transient opening and closing of tumor vasculature result in periods of severe oxygen deprivation (hypoxia) followed by reoxygenation. This exerts a positive selective pressure for cells that have lost their sensitivity to killing by reduced oxygen levels. These cells are effectively resistant to hypoxia-induced apoptosis and conventional therapeutic approaches. Here we show hypoxia-induced S-phase arrest results in regions of single-stranded DNA in stalled replication forks and signals the activation of ATR. S-phase cells represent the most sensitive phase of the cell cycle to the stress of hypoxia/reoxygenation. Loss of ATR or inhibition of ATR kinase activity results in a further loss of reproductive viability in S-phase cells when exposed to hypoxic conditions followed by reoxygenation but has little effect on the inhibition of DNA synthesis. This is, at least in part, mediated via Chk1 signaling because loss of Chk1 also results in increased sensitivity to hypoxia/reoxygenation. The observed decrease in reproductive survival is in part because of the accumulation of DNA damage in S-phase cells during hypoxia exposure in the absence of full ATR activity. Therefore, ATR acts to protect stalled replication forks during hypoxia exposure. In conclusion, ATR and Chk1 play critical roles in the cellular response to hypoxia/reoxygenation, and inhibitors of ATR and Chk1 represent new hypoxic cell cytotoxins.