Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA.
Pharmacol Ther. 2012 Mar;133(3):334-50. doi: 10.1016/j.pharmthera.2011.11.010. Epub 2011 Dec 14.
DNA is under constant assault from genotoxic agents which creates different kinds of DNA damage. The precise replication of the genome and the continuous surveillance of its integrity are critical for survival and the avoidance of carcinogenesis. Cells have evolved an arsenal of repair pathways and cell cycle checkpoints to detect and repair DNA damage. When repair fails, typically cell cycle progression is halted and apoptosis is initiated. Here, we review the different sources and types of DNA damage including DNA replication stress and oxidative stress, the repair pathways that cells utilize to repair damaged DNA, and discuss their biological significance, especially with reference to cancer induction and cancer therapy. We also describe the main methodologies currently used for the detection of DNA damage with their strengths and limitations. We conclude with an outline as to how this information can be used to identify novel pharmacological targets for DNA repair pathways or enhancers of DNA damage to develop improved treatment strategies that will benefit cancer patients.
DNA 不断受到遗传毒性物质的攻击，从而产生各种类型的 DNA 损伤。基因组的精确复制和对其完整性的持续监测对生存和避免致癌作用至关重要。细胞已经进化出了一系列的修复途径和细胞周期检查点，以检测和修复 DNA 损伤。当修复失败时，通常会停止细胞周期的进展，并启动细胞凋亡。在这里，我们回顾了不同来源和类型的 DNA 损伤，包括 DNA 复制应激和氧化应激、细胞用来修复受损 DNA 的修复途径，并讨论了它们的生物学意义，特别是参考了癌症的诱导和癌症治疗。我们还描述了目前用于检测 DNA 损伤的主要方法及其优缺点。最后，我们概述了如何利用这些信息来识别 DNA 修复途径的新型药理学靶点或 DNA 损伤增强剂，以开发改善的治疗策略，使癌症患者受益。
