Hypoxic activation of ATR and the suppression of the initiation of DNA replication through cdc6 degradation.
Hypoxic activation of ATR and the suppression of the initiation of DNA replication through cdc6 degradation.
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DOI：
10.1038/onc.2011.585
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发表时间：
2012-09-06
期刊：
影响因子：
8
通讯作者：
Gardner, L. B.
中科院分区：
文献类型：
--
作者：
Martin, L.;Rainey, M.;Santocanale, C.;Gardner, L. B.
许多严重缺氧的细胞无法启动DNA复制，但这种观察到的机制尚不清楚。具体地说，尽管共济失调-毛细血管扩张-Rad3相关(ATR)激酶已被证明在低氧细胞中被激活，但一些研究尚未能够证明ATR激活在这些细胞中的下游后果。通过明确定义缺氧细胞中的DNA复制起始检查点，我们现在证明ATR负责激活该检查点。我们发现，ATR的低氧激活导致了cdc25a磷酸酶的磷酸化依赖的降解。在低氧细胞中，ATR下调cdc25a蛋白，使cdk2的磷酸化和活性降低，从而导致APC/CCdh1对cdc6的降解。当ATR耗尽时，这些事件不会在缺氧细胞中发生，DNA复制的启动保持不变。因此，我们提出了一种新的cdc6调控机制，其中ATR可以通过调节APC/CCdh1对cdc6的调控而发挥核心作用，抑制DNA复制的启动。这个模型提供了对缺氧性肿瘤的生物学和治疗的洞察力。
Many severely hypoxic cells fail to initiate DNA replication, but the mechanism underlying this observation is unknown. Specifically, while the ataxia-telangiectasia-rad3 related (ATR) kinase has been shown to be activated in hypoxic cells, several studies have not been able to document down-stream consequences of ATR activation in these cells. By clearly defining the DNA replication initiation checkpoint in hypoxic cells, we now demonstrate that ATR is responsible for activating this checkpoint. We show that the hypoxic activation of ATR leads to the phosphorylation dependent degradation of the cdc25a phosphatase. Down regulation of cdc25a protein by ATR in hypoxic cells decreases CDK2 phosphorylation and activity, which results in the degradation of cdc6 by APC/CCdh1. These events do not occur in hypoxic cells when ATR is depleted, and the initiation of DNA replication is maintained. We therefore present a novel mechanism of cdc6 regulation in which ATR can play a central role in inhibiting the initiation of DNA replication via the regulation of cdc6 by APC/CCdh1. This model provides insight into the biology and therapy of hypoxic tumors.
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影响因子：
56.9
作者：
Cortez, D;Wang, Y;Elledge, SJ
通讯作者：
Elledge, SJ
影响因子：
16
作者：
Costanzo, V;Shechter, D;Gautier, J
通讯作者：
Gautier, J
影响因子：
11.2
作者：
Hammond, EM;Dorie, MJ;Giaccia, AJ
通讯作者：
Giaccia, AJ
影响因子：
11.4
作者：
Koshiji, M;Kageyama, Y;Huang, LE
通讯作者：
Huang, LE
DOI：
10.1016/0005-2787(80)90147-1
发表时间：
1980-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
KAUFMANN, WK;CLEAVER, JE;PAINTER, RB
通讯作者：
PAINTER, RB