H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase
H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase
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DOI：
10.1093/carcin/bgm157
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发表时间：
2007-11-01
期刊：
影响因子：
4.7
通讯作者：
Ljungman, Mats
中科院分区：
文献类型：
--
作者：
Hanasoge, Sheela;Ljungman, Mats
有研究表明，组蛋白变体H2AX在紫外线照射后的磷酸化是由复制叉与紫外线诱导的大体积病变碰撞引起的DNA双链断裂触发的。最近，有研究表明，紫外线诱导的H2AX磷酸化也可以发生在s期之外，但这种与复制无关的诱导机制尚不清楚。在这项研究中，我们发现H2AX在紫外线照射后的磷酸化是由DNA修复中间体触发的，并且在细胞周期的所有阶段都被诱导。抑制DNA修复合成的DNA修复中间体的积累导致H2AX磷酸化在修复熟练而非修复缺陷的着色性干皮a细胞中显著增加。利用PI(3)样激酶家族蛋白激酶的化学抑制剂以及共济失调毛细血管扩张突变和Rad-3相关（ATR）缺陷的Seckel综合征细胞和共济失调毛细血管扩张突变缺陷的毛细血管扩张细胞，我们发现修复中间体积累诱导的H2AX磷酸化主要是由ATR激酶介导的。我们提出了一种紫外线诱导H2AX磷酸化的模型，除了复制阻断外，DNA修复中间体通过ATR激酶触发H2AX磷酸化。
It has been suggested that phosphorylation of the histone variant H2AX after ultraviolet light (UV) irradiation is triggered by DNA double-strand breaks induced as replication forks collide with UV-induced bulky lesions. More recently, it has been shown that UV-induced H2AX phosphorylation can also occur outside of S-phase, but the mechanism for this replication-independent induction is not well understood. In this study, we show that H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is induced in all phases of the cell cycle. Accumulation of DNA repair intermediates by inhibition of DNA repair synthesis resulted in a marked increase of H2AX phosphorylation in repair proficient but not repair-deficient xeroderma pigmentosum-A cells. Using chemical inhibitors of the PI(3)-like kinase family of protein kinases as well as ataxia telangiectasia mutated and Rad-3 related (ATR)-deficient Seckel syndrome cells and ataxia telangiectasia mutated-deficient ataxia telangiectasia cells, we show that the H2AX phosphorylation induced by accumulation of repair intermediates is mediated primarily by the ATR kinase. We suggest a model for UV light-induced phosphorylation of H2AX where in addition to replication blockage, DNA repair intermediates trigger H2AX phosphorylation via the ATR kinase.