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首页> 外文期刊>Cancer letters >DNA damage-induced cell death: From specific DNA lesions to the DNA damage response and apoptosis
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DNA damage-induced cell death: From specific DNA lesions to the DNA damage response and apoptosis

机译：DNA损伤诱导的细胞死亡：从特定的DNA损伤到DNA损伤反应和凋亡

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摘要

DNA damaging agents are potent inducers of cell death triggered by apoptosis. Since these agents induce a plethora of different DNA lesions, it is firstly important to identify the specific lesions responsible for initiating apoptosis before the apoptotic executing pathways can be elucidated. Here, we describe specific DNA lesions that have been identified as apoptosis triggers, their repair and the signaling provoked by them. We discuss methylating agents such as temozolomide, ionizing radiation and cisplatin, all of them are important in cancer therapy. We show that the potentially lethal events for the cell are O6-methylguanine adducts that are converted by mismatch repair into DNA double-strand breaks (DSBs), non-repaired N-methylpurines and abasic sites as well as bulky adducts that block DNA replication leading to DSBs that are also directly induced following ionizing radiation. Transcriptional inhibition may also contribute to apoptosis. Cells are equipped with sensors that detect DNA damage and relay the signal via kinases to executors, who on their turn evoke a process that inhibits cell cycle progression and provokes DNA repair or, if this fails, activate the receptor and/or mitochondrial apoptotic cascade. The main DNA damage recognition factors MRN and the PI3 kinases ATM, ATR and DNA-PK, which phosphorylate a multitude of proteins and thus induce the DNA damage response (DDR), will be discussed as well as the downstream players p53, NF-κB, Akt and survivin. We review data and models describing the signaling from DNA damage to the apoptosis executing machinery and discuss the complex interplay between cell survival and death.
机译：DNA破坏剂是由凋亡引发的细胞死亡的有效诱导剂。由于这些试剂可诱导大量不同的DNA损伤，因此首先重要的是在阐明凋亡执行途径之前鉴定引起细胞凋亡的具体损伤。在这里，我们描述了特定的DNA损伤，这些损伤已被确定为凋亡的诱因，它们的修复以及它们引起的信号传导。我们讨论了甲基化剂，如替莫唑胺，电离辐射和顺铂，它们在癌症治疗中都很重要。我们显示该细胞的潜在致命事件是O6-甲基鸟嘌呤加合物，它们通过错配修复被转换成DNA双链断裂（DSBs），未修复的N-甲基嘌呤和无碱基位点以及阻止DNA复制领先的庞大的加合物。也会在电离辐射后直接诱发的DSB。转录抑制也可能导致细胞凋亡。细胞配备有检测DNA损伤并通过激酶将信号传递给执行者的传感器，执行者依次引发抑制细胞周期进程并引发DNA修复的过程，如果失败，则激活受体和/或线粒体凋亡级联反应。将讨论主要的DNA损伤识别因子MRN和PI3激酶ATM，ATR和DNA-PK，这些蛋白会磷酸化多种蛋白质，从而诱导DNA损伤反应（DDR），以及下游分子p53，NF-κB ，Akt和survivin。我们审查数据和模型描述从DNA损伤到凋亡执行机制的信号，并讨论细胞存活与死亡之间的复杂相互作用。

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