CREB-binding protein regulates Ku70 acetylation in response to ionization radiation in neuroblastoma.
CREB-binding protein regulates Ku70 acetylation in response to ionization radiation in neuroblastoma.
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DOI：
10.1158/1541-7786.mcr-12-0065
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发表时间：
2013-02
期刊：
影响因子：
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通讯作者：
Kwok RP
中科院分区：
文献类型：
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作者：
Subramanian C;Hada M;Opipari AW Jr;Castle VP;Kwok RP
Ku70最初被描述为自身抗原，但它也在细胞核中作为DNA修复蛋白，并通过与细胞质中的Bax结合，阻断Bax介导的细胞死亡，作为抗凋亡蛋白。在神经母细胞瘤（NB）细胞中，Ku70与Bax的结合受Ku70乙酰化调节，使得增加Ku70乙酰化导致Bax释放，触发细胞死亡。虽然调节胞质Ku70乙酰化对细胞存活很重要，但核Ku70乙酰化在DNA修复中的作用尚不清楚。在这里，我们证明，Ku70乙酰化在核CREB结合蛋白（CBP）的调节，Ku70乙酰化在NB细胞的DNA修复中起着重要作用。我们用电离辐射处理NB细胞，并测量DNA修复活性以及Ku70乙酰化状态。NB细胞经电离辐射后，胞质和核内Ku70均发生乙酰化。有趣的是，细胞质Ku70被重新分配到细胞核照射后。在NB细胞中，耗尽CBP导致NB细胞中Ku70乙酰化减少，并增强DNA修复活性，表明核Ku70乙酰化可能在DNA修复中具有抑制作用。这些结果为以下假设提供了支持：通过抑制去乙酰化酶来增强Ku70乙酰化，可能会增强NB细胞中电离辐射的效果。
Ku70 was originally described as an auto-antigen, but it also functions as DNA repair protein in the nucleus and as an anti-apoptotic protein by binding to Bax in the cytoplasm, blocking Bax-mediated cell death. In neuroblastoma (NB) cells, Ku70’s binding with Bax is regulated by Ku70 acetylation such that increasing Ku70 acetylation results in Bax release, triggering cell death. While regulating cytoplasmic Ku70 acetylation is important for cell survival, the role of nuclear Ku70 acetylation in DNA repair is unclear. Here we demonstrated that Ku70 acetylation in the nucleus is regulated by the CREB-binding protein (CBP), and that Ku70 acetylation plays an important role in DNA repair in NB cells. We treated NB cells with ionization radiation and measured DNA repair activity as well as Ku70 acetylation status. Cytoplasmic and nuclear Ku70 were acetylated after ionization radiation in NB cells. Interestingly, cytoplasmic Ku70 was redistributed to the nucleus following irradiation. Depleting CBP in NB cells results in reducing Ku70 acetylation and enhancing DNA repair activity in NB cells suggesting nuclear Ku70 acetylation may have an inhibitory role in DNA repair. These results provide support for the hypothesis that enhancing Ku70 acetylation, through deacetylase inhibition, may potentiate the effect of ionization radiation in NB cells.