Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Mutat Res. 2010 Apr-Jun;704(1-3):152-9. doi: 10.1016/j.mrrev.2009.12.005. Epub 2010 Jan 8.
Genome stability is essential for maintaining cellular and organismal homeostasis, but it is subject to many threats. One ubiquitous threat is from a class of compounds known as reactive oxygen species (ROS), which can indiscriminately react with many cellular biomolecules including proteins, lipids, and DNA to produce a variety of oxidative lesions. These DNA oxidation products are a direct risk to genome stability, and of particular importance are oxidative clustered DNA lesions (OCDLs), defined as two or more oxidative lesions present within 10 bp of each other. ROS can be produced by exposure of cells to exogenous environmental agents including ionizing radiation, light, chemicals, and metals. In addition, they are produced by cellular metabolism including mitochondrial ATP generation. However, ROS also serve a variety of critical cellular functions and optimal ROS levels are maintained by multiple cellular antioxidant defenses. Oxidative DNA lesions can be efficiently repaired by base excision repair or nucleotide excision repair. If ROS levels increase beyond the capacity of its antioxidant defenses, the cell's DNA repair capacity can become overwhelmed, leading to the accumulation of oxidative DNA damage products including OCDLs, which are more difficult to repair than individual isolated DNA damage products. Here we focus on the induction and repair of OCDLs and other oxidatively induced DNA lesions. If unrepaired, these lesions can lead to the formation of mutations, DNA DSBs, and chromosome abnormalities. We discuss the roles of these lesions in human pathologies including aging and cancer, and in bystander effects.
基因组稳定性对于维持细胞和机体的内稳态至关重要，但它也面临着许多威胁。其中一种普遍存在的威胁来自一类被称为活性氧（ROS）的化合物，它们可以无差别地与许多细胞生物分子反应，包括蛋白质、脂质和 DNA，产生各种氧化损伤。这些 DNA 氧化产物直接威胁到基因组的稳定性，特别是氧化簇集 DNA 损伤（OCDL），其定义为彼此之间相距 10 个碱基对以内的两个或多个氧化损伤。ROS 可以通过细胞暴露于外源性环境因素如电离辐射、光、化学物质和金属而产生。此外，它们还通过细胞代谢产生，包括线粒体 ATP 的生成。然而，ROS 也具有多种关键的细胞功能，细胞内有多种抗氧化防御机制来维持最佳的 ROS 水平。氧化的 DNA 损伤可以通过碱基切除修复或核苷酸切除修复有效地修复。如果 ROS 水平超过其抗氧化防御能力，细胞的 DNA 修复能力就会不堪重负，导致氧化 DNA 损伤产物（包括 OCDL）的积累，这些产物比单个孤立的 DNA 损伤产物更难修复。在这里，我们重点关注 OCDL 和其他氧化诱导的 DNA 损伤的诱导和修复。如果未修复，这些损伤可导致突变、DNA DSB 和染色体异常的形成。我们讨论了这些损伤在人类病理学（包括衰老和癌症）和旁观者效应中的作用。
