DNA单链断裂修复机制促进CAF-1介导的组蛋白在氧化性DNA链断裂处沉积
The DNA Single-Strand Break Repair Machinery Facilitates CAF-1-Mediated Histone Deposition at Oxidative DNA Strand Breaks
摘要：
细胞中不断出现氧化性DNA单链断裂，其修复缺陷与神经系统疾病有关。虽然在了解染色体单链断裂如何修复方面取得了很大进展，但对伴随这一过程的染色质结构变化知之甚少。在这里，我们表明，新生的重组组蛋白H3.1蛋白的积累，并沉积到染色质的DNA链断裂在静止的人类细胞氧化应激后的网站，和单链断裂修复机制的核心组件是需要这个过程。我们发现，SSBR传感器和支架蛋白聚（ADP-核糖）聚合酶和XRCC 1促进染色质组装因子-1（CAF-1）在氧化DNA链断裂位点的积累，这反过来又介导组蛋白H3.1的沉积。我们还证明，CAF-1的耗竭减缓了氧化应激后静止细胞中DNA链断裂修复的总体速率，表明单链断裂修复和组蛋白沉积是紧密协调的过程。这些数据描述了DNA单链断裂修复机制的新作用，并暗示组蛋白周转是静止细胞对氧化损伤反应的核心组成部分。
英文摘要：
Oxidative DNA single strand breaks arise continuously in cells and defects in their repair have been implicated in neurological disease. While much progress has been made in understanding how chromosomal single strand breaks are repaired little is known about the changes chromatin structure that accompany this process. Here, we show that nascent recombinant histone H3.1 protein accumulates and is deposited into chromatin at sites of DNA strand breakage in quiescent human cells following oxidative stress, and that core components of the single-strand break repair machinery are required for this process. We show that the SSBR sensor and scaffold proteins poly (ADP-ribose) polymerase and XRCC1 facilitate accumulation of chromatin assembly factor-1 (CAF-1) at sites of oxidative DNA strand breakage, which in turn mediates the deposition of Histone H3.1. We also demonstrate that depletion of CAF-1 slows global rates of DNA strand break repair in quiescent cells following oxidative stress, demonstrating that single-strand break repair and histone deposition are tightly coordinated processes. These data describe a novel role for the DNA singlestrand break repair machinery and implicate histone turnover as a core component of the cellular response of quiescent cells to oxidative damage.
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