Subpathways of nucleotide excision repair and their regulation
Subpathways of nucleotide excision repair and their regulation
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DOI：
10.1038/sj.onc.1206096
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发表时间：
2002-12-16
期刊：
影响因子：
8
通讯作者：
Hanawalt, PC
中科院分区：
文献类型：
--
作者：
Hanawalt, PC
核苷酸切除修复提供了一个重要的细胞防御对各种结构无关的DNA改变。大多数这些改变，如果不修复，可能会导致诱变，肿瘤发生，发育异常，以及细胞致死性。核苷酸切除修复有两条途径：全基因组修复（GGR）和转录偶联修复（TCR），后者对表达基因中转录的DNA链具有选择性。一些参与识别DNA损伤的蛋白质（包括RNA聚合酶）也对DNA二级结构特征的自然变异有反应。未受损DNA中的无偿修复事件可能会导致基因组不稳定。然而，GGR的损伤识别酶通常维持在非常低的水平，除非细胞受到基因组应激。GGR在E.在人细胞中通过激活的p53肿瘤抑制因子。人类细胞中的这些可诱导反应是重要的，因为它们已被证明在人类环境暴露的水平上对化学致癌物DNA损伤起作用。有趣的是，大多数啮齿动物组织缺乏p53依赖性GGR途径。由于啮齿动物被用作环境癌症风险评估的替代物，因此我们必须了解它们在DNA修复和对环境基因毒素的致癌反应方面与人类的差异。在终末分化的哺乳动物细胞的情况下，出现了一种新的范例，其中GGR被减弱，但表达基因的两条链都被有效修复。
Nucleotide excision repair provides an important cellular defense against a large variety of structurally unrelated DNA alterations. Most of these alterations, if unrepaired, may contribute to mutagenesis, oncogenesis, and developmental abnormalities, as well as cellular lethality. There are two subpathways of nucleotide excision repair; global genomic repair (GGR) and transcription coupled repair (TCR), that is selective for the transcribed DNA strand in expressed genes. Some of the proteins involved in the recognition of DNA damage (including RNA polymerase) are also responsive to natural variations in the secondary structural features of DNA. Gratuitous repair events in undamaged DNA might then contribute to genomic instability. However, damage recognition enzymes for GGR are normally maintained at very low levels unless the cells are genomically stressed. GGR is controlled through the SOS stress response in E. coli and through the activated p53 tumor suppressor in human cells. These inducible responses in human cells are important, as they have been shown to operate upon chemical carcinogen DNA damage at levels to which humans are environmentally exposed. Interestingly, most rodent tissues are deficient in the p53-dependent GGR pathway. Since rodents are used as surrogates for environmental cancer risk assessment, it is essential that we understand how they differ from humans with respect to DNA repair and oncogenic responses to environmental genotoxins. In the case of terminally differentiated mammalian cells, a new paradigm has appeared in which GGR is attenuated but both strands of expressed genes are repaired efficiently.