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H2AX Is Required for Cell Cycle Arrest via the p53/p21 Pathway

机译：通过p53 / p21途径进行细胞周期阻滞需要H2AX

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Phosphorylation of H2AX (γH2AX) is an early sign of DNA damage induced by replication stalling. However, the role of H2AX in the repair of this type of DNA damage is still unclear. In this study, we used an inactivated adeno-associated virus (AAV) to induce a stalled replication fork signal and investigate the function of γH2AX. The cellular response to AAV provides a unique model to study γH2AX function, because the infection causes pannuclear H2AX phosphorylation without any signs of damage to the host genome. We found that pannuclear γH2AX formation is a result of ATR overactivation and diffusion but is independent of ATM. The inhibition of H2AX with RNA interference or the use of H2AX-deficient cells showed that γH2AX is dispensable for the formation and maintenance of DNA repair foci induced by stalled replication. However, in the absence of H2AX, the AAV-containing cells showed proteosome-dependent degradation of p21, followed by caspase-dependent mitotic catastrophe. In contrast, H2AX-proficient cells as well as H2AX-complemented H2AX?/? cells reacted by increasing p21 levels and arresting the cell cycle. The results establish a new role for H2AX in the p53/p21 pathway and indicate that H2AX is required for p21-induced cell cycle arrest after replication stalling.
机译：H2AX（γH2AX）的磷酸化是复制停滞引起的DNA损伤的早期迹象。但是，H2AX在修复此类DNA损伤中的作用仍不清楚。在这项研究中，我们使用灭活的腺伴随病毒（AAV）来诱导停滞的复制叉信号并研究γH2AX的功能。对AAV的细胞反应为研究γH2AX功能提供了独特的模型，因为感染引起全核H2AX磷酸化，而没有损坏宿主基因组的迹象。我们发现全核γH2AX的形成是ATR过度活化和扩散的结果，但与ATM无关。 RNA干扰对H2AX的抑制作用或使用H2AX缺陷型细胞的研究表明，γH2AX对于停滞复制诱导的DNA修复灶的形成和维持是必不可少的。但是，在没有H2AX的情况下，含AAV的细胞表现出p21的蛋白体依赖性降解，然后是caspase依赖性的有丝分裂灾难。相反，H2AX富裕的细胞以及H2AX互补的H2AX α/β细胞通过增加p21水平和阻止细胞周期而发生反应。结果确立了H2AX在p53 / p21途径中的新作用，并表明复制停滞后p21诱导的细胞周期停滞需要H2AX。

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