Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Winterthurerstrasse 260, CH-8057 Zürich, Switzerland.
Mutat Res. 2010 Mar 1;685(1-2):21-8. doi: 10.1016/j.mrfmmm.2009.08.005. Epub 2009 Aug 15.
The recognition and subsequent repair of DNA damage are essential reactions for the maintenance of genome stability. A key general sensor of DNA lesions is xeroderma pigmentosum group C (XPC) protein, which recognizes a wide variety of helix-distorting DNA adducts arising from ultraviolet (UV) radiation, genotoxic chemicals and reactive metabolic byproducts. By detecting damaged DNA sites, this unique molecular sensor initiates the global genome repair (GGR) pathway, which allows for the removal of all the aforementioned lesions by a limited repertoire of excision factors. A faulty GGR activity causes the accumulation of DNA adducts leading to mutagenesis, carcinogenesis, neurological degeneration and other traits of premature aging. Recent findings indicate that XPC protein achieves its extraordinary substrate versatility by an entirely indirect readout strategy implemented in two clearly discernible stages. First, the XPC subunit uses a dynamic sensor interface to monitor the double helix for the presence of non-hydrogen-bonded bases. This initial screening generates a transient nucleoprotein intermediate that subsequently matures into the ultimate recognition complex by trapping undamaged nucleotides in the abnormally oscillating native strand, in a way that no direct contacts are made between XPC protein and the offending lesion itself. It remains to be elucidated how accessory factors like Rad23B, centrin-2 or the UV-damaged DNA-binding complex contribute to this dynamic two-stage quality control process.
DNA 损伤的识别和随后的修复是维持基因组稳定性的必要反应。一种关键的通用 DNA 损伤传感器是着色性干皮病组 C（XPC）蛋白，它可以识别出各种由紫外线（UV）辐射、遗传毒性化学物质和反应性代谢副产物引起的螺旋扭曲 DNA 加合物。通过检测受损的 DNA 位点，这种独特的分子传感器启动了全基因组修复（GGR）途径，该途径允许通过有限的切除因子去除所有上述损伤。GGR 活性的缺陷会导致 DNA 加合物的积累，从而导致突变、致癌、神经退行性变和其他早衰特征。最近的研究结果表明，XPC 蛋白通过两种明显可区分的阶段实施的完全间接读出策略来实现其非凡的底物多样性。首先，XPC 亚基使用动态传感器界面来监测双螺旋中非氢键结合的碱基的存在。这种初始筛选产生了一个瞬时核蛋白中间体，随后通过将未受损的核苷酸困在异常摆动的天然链中，将其成熟为最终的识别复合物，从而实现了这种成熟，在这种情况下，XPC 蛋白与有问题的损伤本身之间没有直接接触。尚不清楚辅助因子（如 Rad23B、中心体-2 或紫外线损伤 DNA 结合复合物）如何有助于这种动态两阶段质量控制过程。
