National Institute of Public Health and the Environment, Laboratory for Health Protection Research, Bilthoven, The Netherlands.
Mutat Res. 2011 Nov-Dec;728(3):107-17. doi: 10.1016/j.mrrev.2011.07.001. Epub 2011 Jul 7.
The accumulation of DNA damage is a slow but hazardous phenomenon that may lead to cell death, accelerated aging features and cancer. One of the most versatile and important defense mechanisms against the accumulation of DNA damage is nucleotide excision repair (NER), in which the Xeroderma pigmentosum group C (XPC) protein plays a prominent role. NER can be divided into global genome repair (GG-NER) and transcription coupled repair (TC-NER). XPC is a key factor in GG-NER where it functions in DNA damage recognition and after which the repair machinery is recruited to eliminate the DNA damage. Defective XPC functioning has been shown to result in a cancer prone phenotype, in human as well as in mice. Mutation accumulation in XPC deficient mice is accelerated and increased, resulting in an increased tumor incidence. More recently XPC has also been linked to functions outside of NER since XPC deficient mice show a divergent tumor spectrum compared to other NER deficient mouse models. Multiple in vivo and in vitro experiments indicate that XPC appears to be involved in the initiation of several DNA damage-induced cellular responses. XPC seems to function in the removal of oxidative DNA damage, redox homeostasis and cell cycle control. We hypothesize that this combination of increased oxidative DNA damage sensitivity, disturbed redox homeostasis together with inefficient cell cycle control mechanisms are causes of the observed increased cancer susceptibility in oxygen exposed tissues. Such a phenotype is absent in other NER-deficient mice, including Xpa.
DNA 损伤的积累是一个缓慢但危险的现象，可能导致细胞死亡、加速衰老特征和癌症。核苷酸切除修复 (NER) 是对抗 DNA 损伤积累的最通用和最重要的防御机制之一，其中 Xeroderma pigmentosum 组 C (XPC) 蛋白起着突出的作用。NER 可分为全基因组修复 (GG-NER) 和转录偶联修复 (TC-NER)。XPC 是 GG-NER 的关键因素，它在 DNA 损伤识别中发挥作用，然后修复机制被招募以消除 DNA 损伤。已经表明，XPC 功能缺陷会导致癌症易感性表型，无论是在人类还是在小鼠中都是如此。XPC 缺陷小鼠的突变积累加速且增加，导致肿瘤发病率增加。最近，XPC 也与 NER 之外的功能相关，因为 XPC 缺陷小鼠显示出与其他 NER 缺陷小鼠模型不同的肿瘤谱。多项体内和体外实验表明，XPC 似乎参与了几种 DNA 损伤诱导的细胞反应的启动。XPC 似乎在清除氧化 DNA 损伤、氧化还原平衡和细胞周期控制中发挥作用。我们假设，这种增加的氧化 DNA 损伤敏感性、氧化还原平衡失调以及低效的细胞周期控制机制的组合是观察到的在暴露于氧气的组织中增加的癌症易感性的原因。这种表型在其他 NER 缺陷小鼠中不存在，包括 Xpa。
