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Molecular and Cellular Biology, August 2003, p. 5755-5767, Vol. 23, No. 16
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.16.5755-5767.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Xeroderma Pigmentosum Group A Protein Loads as a Separate Factor onto DNA Lesions

Suzanne Rademakers,1 Marcel Volker,2 Deborah Hoogstraten,1 Alex L. Nigg,3 Martijn J. Moné,4 Albert A. van Zeeland,2 Jan H. J. Hoeijmakers,1 Adriaan B. Houtsmuller,3 and Wim Vermeulen1*

Center for Biomedical Genetics, Medical Genetic Center-Department of Cell Biology and Genetics,1 Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, 3000 DR Rotterdam,3 MGC-Department of Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Center, 2333 AL Leiden,2 Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands4

Received 28 March 2003/ Returned for modification 25 April 2003/ Accepted 23 May 2003

Nucleotide excision repair (NER) is the main DNA repair pathway in mammals for removal of UV-induced lesions. NER involves the concerted action of more than 25 polypeptides in a coordinated fashion. The xeroderma pigmentosum group A protein (XPA) has been suggested to function as a central organizer and damage verifier in NER. How XPA reaches DNA lesions and how the protein is distributed in time and space in living cells are unknown. Here we studied XPA in vivo by using a cell line stably expressing physiological levels of functional XPA fused to green fluorescent protein and by applying quantitative fluorescence microscopy. The majority of XPA moves rapidly through the nucleoplasm with a diffusion rate different from those of other NER factors tested, arguing against a preassembled XPA-containing NER complex. DNA damage induced a transient (~5-min) immobilization of maximally 30% of XPA. Immobilization depends on XPC, indicating that XPA is not the initial lesion recognition protein in vivo. Moreover, loading of replication protein A on NER lesions was not dependent on XPA. Thus, XPA participates in NER by incorporation of free diffusing molecules in XPC-dependent NER-DNA complexes. This study supports a model for a rapid consecutive assembly of free NER factors, and a relatively slow simultaneous disassembly, after repair.

* Corresponding author. Mailing address: CBG, MGC-Department of Cell Biology and Genetics, Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. Phone: 31 10 4087194. Fax: 31 10 4089468. E-mail: w.vermeulen{at}erasmusmc.nl.

Molecular and Cellular Biology, August 2003, p. 5755-5767, Vol. 23, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.16.5755-5767.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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