DNA damage-triggered apoptosis: critical role of DNA repair, double-strand breaks, cell proliferation and signaling
DNA damage-triggered apoptosis: critical role of DNA repair, double-strand breaks, cell proliferation and signaling
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DOI：
10.1016/s0006-2952(03)00510-0
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发表时间：
2003-10-15
影响因子：
5.8
通讯作者：
Kaina, B
中科院分区：
文献类型：
--
作者：
Kaina, B
遗传毒性DNA损伤剂可同时激活膜死亡受体和内源性线粒体损伤途径，通过细胞凋亡导致细胞死亡。在这里，细胞的凋亡反应表现出各种DNA修复途径的缺陷，如烷基转移酶。对碱基切除修复、核苷酸切除修复和错配修复进行了综述。HSVtk/Ganciclovir和VZV/BVDU自杀系统也将被讨论。有数据表明，关键的DNA损伤通过激活成纤维细胞中的线粒体损伤途径，以DNA复制依赖的方式触发细胞凋亡。DNA双链断裂(DSB)是DNA复制过程中由原发DNA损伤引起的常见的终极细胞凋亡损伤。因此，DNA复制是DNA损伤引发的细胞凋亡的必要组成部分，至少在用基因毒素处理的成纤维细胞中是这样，而不是本身诱导DSB。对于诱导O-6-甲基鸟嘌呤的甲基化试剂，另一个要求是错配修复引发DSB的形成，从而触发Bcl-2下降和caspase-9/-3激活。这与P53无关，因为研究中的大多数修复缺陷细胞系都发生了P53突变。此外，P53基因敲除的成纤维细胞对甲基化试剂和紫外线更敏感，而不是建议P53在这个细胞系统中发挥保护作用，而不是促凋亡作用，可能是通过参与DNA P53 wt细胞的修复。然而，对于淋巴母细胞，P53 wt变异体对DNA损伤更敏感，这表明P53以一种细胞类型特异性的方式参与了凋亡信号的传递。此外，还将讨论拓扑异构酶11抑制剂和c-Fos/AP-1在细胞凋亡中的作用。(C)2003 Elsevier Inc.保留所有权利。
Genotoxic DNA damaging agents may activate both membrane death receptors and the endogenous mitochondrial damage pathway leading to cell death via apoptosis. Here, apoptotic responses in cells exhibiting a defect in various DNA repair pathways such as alkyltransferase. base excision repair, nucleotide excision repair and mismatch repair are reviewed. The HSVTk/ganciclovir and VZV/BVDU suicide system will also be discussed. Data are available to show that critical DNA damage triggers apoptosis in a DNA replication dependent way by activating the mitochondrial damage pathway in fibroblasts. It is proposed that DNA double-strand breaks (DSBs) are common ultimate apoptosis-triggering lesions arising from primary DNA lesions during DNA replication. Thus, DNA replication is a necessary component in DNA damage-triggered apoptosis, at least in fibroblasts treated with genotoxins not inducing DSBs themselves. For methylating agents inducing O-6- methylguanine, an additional requirement is mismatch repair provoking DSB formation that triggers Bcl-2 decline and caspase-9/-3 activation. This occurs independent of p53 since most of the repair deficient cell lines under study were mutated for p53. Moreover, p53 knockout fibroblasts are more sensitive to methylating agents and UV light than suggesting p53 to play a protective rather than a pro-apoptotic role in this cell system, probably by its involvement in DNA p53 wt cells, , repair. However, for lymphoblastoid cells p53 wt variants are more sensitive to DNA damage indicating that p53 participates in apoptotic signaling in a cell type-specific fashion. The role of topoisomerase 11 inhibitors and c-Fos/AP-1 in apoptosis will also be discussed. (C) 2003 Elsevier Inc. All rights reserved.