The present study was undertaken to determine the significance of histone acetylation versus DNA damage in drug-induced irreversible growth arrest (senescence) and apoptosis. Cellular treatment with the DNA-damaging drugs doxorubicin and cisplatin or with the histone deacetylase inhibitor trichostatin A, led to the finding that all the three drugs induced senescence at concentrations significantly lower than those required for apoptosis. However, only doxorubicin and cisplatin induced activation of H2AX, a marker for double-strand break formation. Interestingly, this occurred mainly at apoptosis and not senescence-inducing drug concentrations, suggesting that non-DNA-damage pathways may be implicated in induction of senescence by these drugs. In agreement with this, chromatin immunoprecipitation experiments indicated that doxorubicin was able to induce acetylation of histone H3 at the promoter of p21/WAF1 only at senescence-inducing concentrations. Collectively, these findings suggest that alteration of chromatin structure by cytotoxic drugs may represent a key mediator of senescence.

中文翻译：

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组蛋白乙酰化与DNA损伤在药物诱导的衰老和凋亡中的作用。

进行本研究以确定组蛋白乙酰化与DNA损伤在药物诱导的不可逆生长停滞（衰老）和细胞凋亡中的重要性。用破坏DNA的药物阿霉素和顺铂或用组蛋白脱乙酰基酶抑制剂曲古抑菌素A进行细胞处理，导致发现所有这三种药物都能以明显低于凋亡所需浓度的浓度诱导衰老。但是，仅阿霉素和顺铂诱导H2AX的活化，H2AX是双链断裂形成的标志。有趣的是，这主要发生在凋亡而不是诱导衰老的药物浓度上，这表明非DNA损伤途径可能与这些药物诱导衰老有关。同意这一点，染色质免疫沉淀实验表明，阿霉素仅在衰老诱导浓度下才能在p21 / WAF1启动子上诱导组蛋白H3的乙酰化。总的来说，这些发现表明细胞毒性药物对染色质结构的改变可能代表了衰老的关键介质。