A Shld1-controlled POT1a provides support for repression of ATR signaling at telomeres through RPA exclusion.
A Shld1-controlled POT1a provides support for repression of ATR signaling at telomeres through RPA exclusion.
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DOI：
10.1016/j.molcel.2010.10.016
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发表时间：
2010-11-12
期刊：
影响因子：
16
通讯作者：
de Lange T
中科院分区：
文献类型：
--
作者：
Gong Y;de Lange T
我们先前提出POT 1通过从单链TTAGGG重复中排除RPA来阻止端粒处的ATR信号传导。在这里，我们使用Shld 1稳定的degron-POT 1a融合（DD-POT 1a）来研究端粒ATR激酶的反应。在不存在Shld 1的情况下，DD-POT 1a降解导致G1和S/G2中ATR途径的快速和可逆激活。ATR和TopBP 1的shRNA可消除ATR信号传导，但ATM激酶或DNA-PKcs的shRNA不影响端粒损伤反应。重要的是，G1和S/G2中的ATR信号被RPA的shRNA减少。在S/G2中，RPA在功能失调的端粒处很容易检测到，并且POT 1a和POT 1b都需要排除RPA并防止ATR激活。在G1期，RPA在功能失调的端粒上的积累明显减少，POT 1a足以抑制ATR信号传导。这些结果支持RPA排除模型在端粒的ATR信号的抑制。
We previously proposed that POT1 prevents ATR signaling at telomeres by excluding RPA from the single-stranded TTAGGG repeats. Here we use a Shld1-stabilized degron-POT1a fusion (DD-POT1a) to study the telomeric ATR kinase response. In the absence of Shld1, DD-POT1a degradation resulted in rapid and reversible activation of the ATR pathway in G1 and S/G2. ATR signaling was abrogated by shRNAs to ATR and TopBP1, but shRNAs to the ATM kinase or DNA-PKcs did not affect the telomere damage response. Importantly, ATR signaling in G1 and S/G2 was reduced by shRNAs to RPA. In S/G2, RPA was readily detectable at dysfunctional telomeres and both POT1a and POT1b were required to exclude RPA and prevent ATR activation. In G1, the accumulation of RPA at dysfunctional telomeres was strikingly less and POT1a was sufficient to repress ATR signaling. These results support an RPA exclusion model for the repression of ATR signaling at telomeres.
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DOI：
10.1126/science.1170633
发表时间：
2009-11-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
de Lange T
通讯作者：
de Lange T
影响因子：
10.5
作者：
Mordes, Daniel A.;Glick, Gloria G.;Cortez, David
通讯作者：
Cortez, David
影响因子：
10.5
作者：
Furuya, K;Poitelea, M;Carr, AM
通讯作者：
Carr, AM
影响因子：
56.9
作者：
Zou, L;Elledge, SJ
通讯作者：
Elledge, SJ
影响因子：
5.3
作者：
Mirzoeva, OK;Petrini, JHJ
通讯作者：
Petrini, JHJ