Versatile DNA damage detection by the global genome nucleotide excision repair protein XPC

作者：Deborah Hoogstraten, Steven Bergink, Jessica M.Y. Ng, Vincent H. M. Verbiest, Martijn S. Luijsterburg, Bart Geverts, Anja Raams, Christoffel Dinant, Jan H.J. Hoeijmakers, Wim Vermeulen, Adriaan B. Houtsmuller · 发表于：Journal of Cell Science · 年份：2008 · DOI：10.1242/jcs.031708 · 被引用次数：121 · 研究领域：DNA Repair Mechanisms、DNA and Nucleic Acid Chemistry、RNA Interference and Gene Delivery

To investigate how the nucleotide excision repair initiator XPC locates DNA damage in mammalian cell nuclei we analyzed the dynamics of GFP-tagged XPC. Photobleaching experiments showed that XPC constantly associates with and dissociates from chromatin in the absence of DNA damage. DNA-damaging agents retard the mobility of XPC, and UV damage has the most pronounced effect on the mobility of XPC-GFP. XPC exhibited a surprising distinct dynamic behavior and subnuclear distribution compared with other NER factors. Moreover, we uncovered a novel regulatory mechanism for XPC. Under unchallenged conditions, XPC is continuously exported from and imported into the nucleus, which is impeded when NER lesions are present. XPC is omnipresent in the nucleus, allowing a quick response to genotoxic stress. To avoid excessive DNA probing by the low specificity of the protein, the steady-state level in the nucleus is controlled by nucleus-cytoplasm shuttling, allowing temporally higher concentrations of XPC in the nucleus under genotoxic stress conditions.