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First published online 5 August 2008
doi: 10.1242/jcs.031708

Journal of Cell Science 121, 2850-2859 (2008)
Published by The Company of Biologists 2008
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Research Article

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

Deborah Hoogstraten1, Steven Bergink1, Jessica M. Y. Ng1,*, Vincent H. M. Verbiest1, Martijn S. Luijsterburg3, Bart Geverts2, Anja Raams1, Christoffel Dinant1,2, Jan H. J. Hoeijmakers1, Wim Vermeulen1,* and Adriaan B. Houtsmuller2,*

1 Department of Cell Biology and Genetics, Erasmus MC Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
2 Department of Pathology (Josephine Nefkens Institute), Erasmus MC Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
3 Swammerdam Institute for Life Sciences, University of Amsterdam, Kruislaan 318, 1098 SM Amsterdam, The Netherlands

* Authors for correspondence (e-mail: w.vermeulen{at}erasmusmc.nl; a.houtsmuller{at}erasmusmc.nl)

Accepted 3 June 2008

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.

Key words: DNA binding, DNA repair, Live cell reaction kinetics




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