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Molecular and Cellular Biology, December 2004, p. 10670-10680, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10670-10680.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Definition of a Short Region of XPG Necessary for TFIIH Interaction and Stable Recruitment to Sites of UV Damage

Fabrizio Thorel,¹ Angelos Constantinou,^1, Isabelle Dunand-Sauthier,¹ Thierry Nouspikel,^1, Philippe Lalle,^1, Anja Raams,² Nicolaas G. J. Jaspers,² Wim Vermeulen,² Mahmud K. K. Shivji,^3,|| Richard D. Wood,^3,¶ and Stuart G. Clarkson^1*

Department of Microbiology and Molecular Medicine, University Medical Centre, Geneva, Switzerland,¹ Department of Cell Biology and Genetics, Erasmus University, Rotterdam, The Netherlands,² Clare Hall Laboratories, Cancer Research UK, South Mimms, Hertfordshire, United Kingdom³

Received 19 July 2004/ Returned for modification 11 August 2004/ Accepted 21 September 2004

XPG is the human endonuclease that cuts 3' to DNA lesions during nucleotide excision repair. Missense mutations in XPG can lead to xeroderma pigmentosum (XP), whereas truncated or unstable XPG proteins cause Cockayne syndrome (CS), normally yielding life spans of <7 years. One XP-G individual who had advanced XP/CS symptoms at 28 years has been identified. The genetic, biochemical, and cellular defects in this remarkable case provide insight into the onset of XP and CS, and they reveal a previously unrecognized property of XPG. Both of this individual's XPG alleles produce a severely truncated protein, but an infrequent alternative splice generates an XPG protein lacking seven internal amino acids, which can account for his very slight cellular UV resistance. Deletion of XPG amino acids 225 to 231 does not abolish structure-specific endonuclease activity. Instead, this region is essential for interaction with TFIIH and for the stable recruitment of XPG to sites of local UV damage after the prior recruitment of TFIIH. These results define a new functional domain of XPG, and they demonstrate that recruitment of DNA repair proteins to sites of damage does not necessarily lead to productive repair reactions. This observation has potential implications that extend beyond nucleotide excision repair.

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* Corresponding author. Mailing address: Department of Microbiology and Molecular Medicine, University Medical Centre, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. Phone: 4122 379 5664. Fax: 4122 379 5702. E-mail: stuart.clarkson{at}medecine.unige.ch.

Present address: Département de Biochimie, Université de Lausanne, 1066 Epalinges, Switzerland.

Present address: Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020.

Present address: Institut de Biologie et Chimie des Protéines, UMR 5086 CNRS/Université Claude Bernard, 69007 Lyon, France.

^|| Present address: MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge CB2 2XZ, United Kingdom.

^¶ Present address: Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213-1863.

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Molecular and Cellular Biology, December 2004, p. 10670-10680, Vol. 24, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.24.10670-10680.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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