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Molecular and Cellular Biology, December 2008, p. 7225-7235, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.00781-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Dissection of the Molecular Defects Caused by Pathogenic Mutations in the DNA Repair Factor XPC{triangledown} ,{dagger}

Bruno M. Bernardes de Jesus,1 Magnar Bjørås,2 Frédéric Coin,1 and Jean Marc Egly1*

Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404 Illkirch Cedex, C. U. Strasbourg, France,1 Department of Molecular Biology, Institute of Medical Microbiology and Centre of Molecular Biology and Neuroscience, University of Oslo, Rikshospitalet Radiumhospitalet HF, Oslo, Norway2

Received 15 May 2008/ Returned for modification 23 July 2008/ Accepted 11 September 2008

XPC is responsible for DNA damage sensing in nucleotide excision repair (NER). Mutations in XPC lead to a defect in NER and to xeroderma pigmentosum (XP-C). Here, we analyzed the biochemical properties behind mutations found within three patients: one amino acid substitution (P334H, XP1MI, and GM02096), one amino acid incorporation in a conserved domain (697insVal, XP8BE, and GM02249), and a stop mutation (R579St, XP67TMA, and GM14867). Using these mutants, we demonstrated that HR23B stabilizes XPC on DNA and protects it from degradation. XPC recruits the transcription/repair factor TFIIH and stimulates its XPB ATPase activity to initiate damaged DNA opening. In an effort to understand the severity of XP-C phenotypes, we also demonstrated that single mutations in XPC perturb other repair processes, such as base excision repair (e.g., the P334H mutation prevents the stimulation of Ogg1 glycosylase because it thwarts the interaction between XPC and Ogg1), thereby leading to a deeper understanding of the molecular repair defect of the XP-C patients.

* Corresponding author. Mailing address: Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404 Illkirch Cedex, C. U. Strasbourg, France. Phone: 33 (0) 3 88 65 34 47. Fax: 33 (0) 3 88 65 32 01. E-mail: egly{at}igbmc.u-strasbg.fr

{triangledown} Published ahead of print on 22 September 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2008, p. 7225-7235, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.00781-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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