Question

求英文翻译。。

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 (also known as TERF2) has a crucial role in end protection through the suppression of ATM activation and the formation of end-to-end chromosome fusions1, 2. Here we address the molecular properties of TRF2 that are both necessary and sufficient to protect chromosome ends in mouse embryonic fibroblasts. 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 the activation of a DNA-damage response (DDR). Next, TRF2 independently suppresses the propagation of DNA-damage signalling downstream of ATM activation. This novel modulation of the DDR at telomeres occurs at the level of the E3 ubiquitin ligase RNF168 (ref. 3). Inhibition of RNF168 at telomeres involves the deubiquitinating 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 DDR proteins at functional telomeres without concurrent induction of detrimental DNA-repair activities.

Answer 1

哺乳动物端粒抑制DNA损伤激活染色体自然末端通过招募的DNA损坏机器，形成一个保护复杂的被称为端粒结合蛋白的特异性抑制剂。在这个复杂的，TRF2（也称为TERF2）在末端保护至关重要的作用，通过ATM激活的抑制和端到端的染色体fusions1形成，2。在这里，我们解决的TRF2是必要的和足够的保护，在小鼠胚胎成纤维细胞的染色体末端的分子特性。我们的数据支持一个两步机制介导的TRF2端保护。首先，TRF2二聚化结构域是必需的抑制ATM激活的关键的第一步，参与了DNA损伤反应的活化（DDR）。接下来，TRF2独立抑制DNA损伤信号的ATM激活下游的传播。这种新颖的调制的DDR在端粒发生在E3泛素连接酶RNF168水平（参考文献3）。在端粒RNF168的抑制涉及泛素酶brcc3和泛素连接酶ubr5，和足以抑制染色体端-端融合。这两个步骤的机制介导的一端TRF2保护有助于解释DDR蛋白在端粒的功能没有有害的DNA修复活动频繁并发感应定位明显的悖论。

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