Klarer Alden C, McGregor W
Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40202, USA.
Crit Rev Eukaryot Gene Expr. 2011;21(4):323-36. doi: 10.1615/critreveukargeneexpr.v21.i4.30.
Cellular DNA is continuously assaulted by chemical and physical agents that arise from both endogenous metabolic processes as well as exogenous insults. Commonly encountered environmental agents include polyaromatic hydrocarbons, polycyclic aromatic amines, the ultraviolet component of sunlight, and ionizing radiation, among many others. Although the kinds of damages and the mechanisms involved in their interaction with DNA vary widely, genotoxic agents alter the structure of DNA in ways that may result in permanent alterations in the DNA sequence or in cell death. To avoid these consequences, cells have evolved countermeasures to reduce the biological consequences of DNA damage. These mechanisms are highly conserved and are present in all eukaryotic cells. In general, cellular responses include the detection of damage, signal transduction to halt cell cycle progression, and the recruitment of repair mechanisms that are tailored to the specific kind of damage. If replication-blocking damage remains when cells enter S-phase, then tolerance mechanisms in the form of complex recombination mechanisms or translesion DNA synthesis using accessory DNA polymerases exist. These mechanisms complete the replication of damaged genomes and suppress cytotoxicity, but at the potential cost of mutagenesis and genomic instability. This review focuses on error-prone mechanisms, including a discussion of the Y-family of DNA polymerases, current concepts of DNA polymerase switching mechanisms, and their relevance to cancer and cancer prevention.
细胞DNA不断受到来自内源性代谢过程以及外源性损伤的化学和物理因素的攻击。常见的环境因素包括多环芳烃、多环芳香胺、阳光中的紫外线成分以及电离辐射等等。尽管DNA损伤的种类及其与DNA相互作用的机制差异很大，但遗传毒性剂会以可能导致DNA序列永久改变或细胞死亡的方式改变DNA结构。为避免这些后果，细胞进化出了应对措施以减少DNA损伤的生物学后果。这些机制高度保守，存在于所有真核细胞中。一般来说，细胞反应包括损伤检测、阻止细胞周期进程的信号转导以及针对特定损伤类型的修复机制的募集。当细胞进入S期时，如果仍存在阻止复制的损伤，那么就会存在以复杂重组机制或使用辅助DNA聚合酶进行跨损伤DNA合成形式的耐受机制。这些机制完成受损基因组的复制并抑制细胞毒性，但可能以诱变和基因组不稳定为代价。本综述重点关注易错机制，包括对DNA聚合酶Y家族的讨论、DNA聚合酶切换机制的当前概念及其与癌症和癌症预防的相关性。
