Phosphorylation of histone H2AX on ser 139 and activation of ATM during oxidative burst in phorbol ester-treated human leukocytes
Phosphorylation of histone H2AX on ser 139 and activation of ATM during oxidative burst in phorbol ester-treated human leukocytes
复制标题
DOI：
10.4161/cc.5.22.3472
复制
发表时间：
2006-11-15
期刊：
影响因子：
4.3
通讯作者：
Darzynkiewicz, Zbigniew
中科院分区：
文献类型：
--
作者：
Tanaka, Toshiki;Halicka, H. Dorota;Darzynkiewicz, Zbigniew
氧化猝发是粒细胞或单核细胞等特殊吞噬细胞通过产生超氧阴离子杀死入侵微生物的一种防御机制。氧化爆发还会导致吞噬细胞的DNA损伤。吞噬细胞是终末分化的细胞，是一些寿命很短的细胞。我们没有发现氧化猝发介导的DNA损伤是否在这类细胞中触发了组蛋白H_2AX-Ser139的磷酸化和突变的毛细血管扩张性共济失调(ATM)的激活，否则这些信号就被用来激活增殖细胞中的DNA修复和检查点通路。我们现在提出的证据表明，佛波酯(PMA)诱导人外周血白细胞的氧化应激与组蛋白H_2AX的强烈磷酸化和ATM的激活有关，这在PMA暴露60分钟后就已经看到了。单个粒细胞、单核细胞和淋巴细胞中的H_2AX和ATM的修饰在caspase激活之前被检测到，因此与诱导细胞凋亡无关。在反应中观察到了很大的细胞间差异，并且这些亚群中只有一小部分细胞表现出H2 AX和ATM修饰。这些数据与早期对氧化爆发期间DNA损伤的观察结果相一致，表明即使在寿命较短的终末分化细胞中，DNA损伤也会触发DNA修复机制的重新启动。淋巴细胞中H_2AX的磷酸化可能反映了来自邻近粒细胞和/或单核细胞的超氧阴离子对其DNA的损伤。
Oxidative burst is a defense mechanism used by specialized phagocytes such as granulocytes or monocytes to kill the invading microorganisms through generation of superoxide anions. Oxidative burst also results in DNA damage of the phagocytes. Phagocytes are terminally differentiated cells, some of very short life-span cells. We could find no reports whether oxidative burst-mediated DNA damage triggers in such cells histone H2AX-Ser139 phosphorylation and activation of Ataxia Telangiectasia Mutated (ATM), the signals otherwise used to activate DNA repair and checkpoint pathways in proliferating cells. We now present the evidence that induction of oxidative stress in human peripheral blood leukocytes by phorbol myristate acetate (PMA) was associated with intense phosphorylation of histone H2AX and with ATM activation, seen already 60 min after exposure to PMA. The modifications of H2AX and ATM in individual granulocytes, monocytes and lymphocytes were detected prior to caspases activation and thus were unrelated to induction of apoptosis. A large intercellular variation in response was observed, and only a fraction of cells in these subpopulations showed H2AX and ATM modifications. The data are compatible with the earlier observations of DNA damage during oxidative burst and suggest that even in terminally differentiated cells that have a short life-span, DNA damage triggers recruitment of the DNA repair machinery. The observed H2AX phosphorylation in lymphocytes may reflect their DNA damage by the superoxide ions propagating from the neighboring granulocytes and/or monocytes.