A two-step mechanism for TRF2-mediated chromosome-end protection.
A two-step mechanism for TRF2-mediated chromosome-end protection.
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DOI：
10.1038/nature11873
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发表时间：
2013-02-28
期刊：
影响因子：
64.8
通讯作者：
Denchi, Eros Lazzerini
中科院分区：
文献类型：
--
作者：
Okamoto, Keiji;Bartocci, Cristina;Ouzounov, Iliana;Diedrich, Jolene K.;Yates, John R., III;Denchi, Eros Lazzerini
哺乳动物端粒通过募集DNA损伤机制的特异性抑制剂来抑制天然染色体末端的DNA损伤活化，所述DNA损伤机制形成称为shelterin的保护性复合物。在这种复合物中，TRF2在末端保护中起着至关重要的作用，因为它需要抑制ATM激活和端对端染色体融合的形成。在这里，我们解决TRF2的分子特性，这是必要的和足够的保护染色体末端。我们的数据支持TRF2介导的末端保护的两步机制。首先，TRF2的二聚化结构域需要抑制ATM激活，ATM激活是DNA损伤反应激活的关键初始步骤。接下来，TRF2独立地抑制ATM活化下游的DNA损伤信号传导的传播。端粒DNA损伤反应的这种新的调节发生在E3泛素连接酶RNF168的水平上。RNF168在端粒处的抑制涉及去泛素化酶BRCC3和泛素连接酶UBR 5，并且足以抑制染色体端到端融合。TRF2介导的末端保护的两步机制有助于解释DNA损伤反应蛋白频繁定位于功能性端粒而不同时诱导有害的DNA修复活性的明显矛盾。
Mammalian telomeres repress DNA damage activation at natural chromosome ends by recruiting specific inhibitors of the DNA damage machinery that form a protective complex termed shelterin. Within this complex, TRF2 plays a crucial role in end-protection as it is required to suppress ATM activation and the formation of end-to-end chromosome fusions. Here, we address the molecular properties of TRF2 that are both necessary and sufficient to protect chromosome ends. Our data support a two-step mechanism for TRF2-mediated end protection. First, the dimerization domain of TRF2 is required to inhibit ATM activation, the key initial step involved in activation of a DNA damage response. Next, TRF2 independently suppresses the propagation of DNA damage signaling downstream of ATM activation. This novel modulation of the DNA damage response at telomeres occurs at the level of the E3 ubiquitin ligase RNF168 . Inhibition of RNF168 at telomeres involves the de-ubiquitinating enzyme BRCC3 and the ubiquitin ligase UBR5 and is sufficient to suppress chromosome end-to-end fusions. This two-step mechanism for TRF2-mediated end protection helps to explain the apparent paradox of frequent localization of DNA damage response proteins at functional telomeres without concurrent induction of detrimental DNA repair activities.
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影响因子：
64.5
作者：
Sfeir A;Kosiyatrakul ST;Hockemeyer D;MacRae SL;Karlseder J;Schildkraut CL;de Lange T
通讯作者：
de Lange T
影响因子：
64.5
作者：
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deLange, T
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Smogorzewska, A;Karlseder, J;de Lange, T
通讯作者：
de Lange, T
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作者：
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通讯作者：
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