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首页> 外文期刊>Cell cycle >Oxidative stress induces cell cycle-dependent Mre11 recruitment, ATM and Chk2 activation and histone H2AX phosphorylation.
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Oxidative stress induces cell cycle-dependent Mre11 recruitment, ATM and Chk2 activation and histone H2AX phosphorylation.

机译：氧化应激诱导细胞周期依赖性Mre11募集，ATM和Chk2激活以及组蛋白H2AX磷酸化。

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摘要

DNA damage response recruits complex molecular machinery involved in DNA repair, arrest of cell cycle progression, and potentially in activation of apoptotic pathway. Among the first responders is the Mre11- (MRN) complex of proteins (Mre11, Rad50, Nbs1), essential for activation of ATM; the latter activates checkpoint kinase 2 (Chk2) and phosphorylates histone H2AX. In the present study the recruitment of Mre11 and phosphorylation of ATM, Chk2 and H2AX (gammaH2AX) detected immunocytochemically were measured by laser scanning cytometry to assess kinetics of these events in A549 cells treated with H(2)O(2). Recruitment of Mre11 was rapid, peaked at 10 min of exposure to the oxidant, and was of similar extent in all phases of the cell cycle. ATM and Chk2 activation as well as H2AX phosphorylation reached maximum levels after 30 min of treatment with H(2)O(2); the extent of phosphorylation of each was most prominent in S-, less in G(1)-, and the least in G(2)M- phase cells. A strong correlation between activation of ATM and Chk2, measured in the same cells, was seen in all phases of the cycle. In untreated cells activated Chk2 and Mre11 were distinctly present in centrosomes while in interphase cells they had characteristic punctate nuclear localization. The punctate expression of activated Chk2 both in untreated and H(2)O(2) treated cells was accentuated when measured as maximal pixel rather than integrated value of immunofluorescence (IF) per nucleus, and was most pronounced in G(1) cells, likely reflecting the function of Chk2 in activating Cdc25A. Subpopulations of G(1) and G(2)M cells with strong maximal pixel of Chk2-Thr68(P) IF in association with centrosomes were present in untreated cultures. Cytometric multiparameter assessment of the DNA damage response utilizing quantitative image analysis that allows one to measure inhomogeneity of fluorochrome distribution (e.g., maximal pixel) offers unique advantage in studies of the response of different cell constituents in relation to cell cycle position.
机译：DNA损伤反应募集了复杂的分子机制，参与了DNA修复，细胞周期进程的停止以及潜在的细胞凋亡途径的激活。在第一个应答者中是Mre11-（MRN）蛋白质复合物（Mre11，Rad50，Nbs1），是ATM激活所必需的。后者激活检查点激酶2（Chk2）并磷酸化组蛋白H2AX。在本研究中，通过激光扫描细胞术测量免疫细胞化学检测的Mre11募集和ATM，Chk2和H2AX（gammaH2AX）的磷酸化，以评估用H（2）O（2）处理的A549细胞中这些事件的动力学。 Mre11的募集迅速，在暴露于氧化剂的10分钟达到峰值，并且在细胞周期的所有阶段都具有相似的程度。用H（2）O（2）处理30分钟后，ATM和Chk2激活以及H2AX磷酸化达到最大水平;每个磷酸化的程度在S-中最显着，在G（1）-中较少，而在G（2）M-相细胞中最少。在周期的所有阶段中，在同一单元中测得的ATM和Chk2激活之间存在很强的相关性。在未经处理的细胞中，活化的Chk2和Mre11明显存在于中心体中，而在相间细胞中，它们具有特征性的点状核定位。以最大像素而不是每个细胞核免疫荧光（IF）的积分值测量时，未处理和H（2）O（2）处理的细胞中激活的Chk2的点状表达均加重，在G（1）细胞中最为明显，可能反映了Chk2在激活Cdc25A中的功能。在未经处理的培养物中，存在带有Chk2-Thr68（P）IF的最大最大像素的G（1）和G（2）M细胞亚群，与中心体相关。利用定量图像分析对DNA损伤反应进行细胞学多参数评估，这种定量图像分析可以测量荧光染料分布的不均匀性（例如最大像素），在研究不同细胞成分对细胞周期位置的反应方面具有独特的优势。

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