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首页> 外文期刊>Molecular and Cellular Biology >Requirement for the Phospho-H2AX Binding Module of Crb2 in Double-Strand Break Targeting and Checkpoint Activation
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Requirement for the Phospho-H2AX Binding Module of Crb2 in Double-Strand Break Targeting and Checkpoint Activation

机译：双链断裂靶向和检查点激活中Crb2的Phospho-H2AX绑定模块的要求

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Activation of DNA damage checkpoints requires the rapid accumulation of numerous factors to sites of genomic lesions, and deciphering the mechanisms of this targeting is central to our understanding of DNA damage response. Histone modification has recently emerged as a critical element for the correct localization of damage response proteins, and one key player in this context is the fission yeast checkpoint mediator Crb2. Accumulation of Crb2 at ionizing irradiation-induced double-strand breaks (DSBs) requires two distinct histone marks, dimethylated H4 lysine 20 (H4K20me2) and phosphorylated H2AX (pH2AX). A tandem tudor motif in Crb2 directly binds H4K20me2, and this interaction is required for DSB targeting and checkpoint activation. Similarly, pH2AX is required for Crb2 localization to DSBs and checkpoint control. Crb2 can directly bind pH2AX through a pair of C-terminal BRCT repeats, but the functional significance of this binding has been unclear. Here we demonstrate that loss of its pH2AX-binding activity severely impairs the ability of Crb2 to accumulate at ionizing irradiation-induced DSBs, compromises checkpoint signaling, and disrupts checkpoint-mediated cell cycle arrest. These impairments are similar to that reported for abolition of pH2AX or mutation of the H4K20me2-binding tudor motif of Crb2. Intriguingly, a combined ablation of its two histone modification binding modules yields a strikingly additive reduction in Crb2 activity. These observations argue that binding of the Crb2 BRCT repeats to pH2AX is critical for checkpoint activity and provide new insight into the mechanisms of chromatin-mediated genome stability.
机译：DNA损伤检查点的激活需要在基因组损伤部位迅速积累多种因素，而破译这种靶向机制对于我们对DNA损伤反应的理解至关重要。组蛋白修饰最近已成为损伤反应蛋白正确定位的关键元素，在这种情况下，裂变酵母检查点介体Crb2是一个关键角色。电离辐射诱导的双链断裂（DSB）处Crb2的积累需要两个不同的组蛋白标记，二甲基化的H4赖氨酸20（H4K20me2）和磷酸化的H2AX（pH2AX）。 Crb2中的串联Tudor基序直接与H4K20me2结合，而这种相互作用是DSB靶向和检查点激活所必需的。同样，将Crb2定位到DSB和检查点控制需要pH2AX。 Crb2可以通过一对C端BRCT重复序列直接结合pH2AX，但是这种结合的功能意义尚不清楚。在这里，我们证明了其pH2AX结合活性的丧失严重损害了Crb2在电离辐射诱导的DSBs上积累的能力，损害了检查点信号传导，并破坏了检查点介导的细胞周期停滞。这些损伤与报道的废除pH2AX或Crb2的H4K20me2结合tudor基序突变有关。有趣的是，其两个组蛋白修饰结合模块的组合消融导致Crb2活性显着加和降低。这些观察结果表明，Crb2 BRCT重复序列与pH2AX的结合对于检查点活性至关重要，并为染色质介导的基因组稳定性机制提供了新的见解。

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