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Article

Dissection of the Molecular Defects Caused by Pathogenic Mutations in the DNA Repair Factor XPC

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Pages 7225-7235 | Received 15 May 2008, Accepted 11 Sep 2008, Published online: 27 Mar 2023
 

Abstract

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.

SUPPLEMENTAL MATERIAL

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

ACKNOWLEDGMENTS

We thank Sascha Feuerhahn, Vincent Mocquet, Colm Ryan, and Renier Velez-Cruz for fruitful discussions and critical reading of the manuscript.

This study was supported by funds from the French League against Cancer (CDP 589111) and the French National Research Agency (NR-05-MRAR-005-01). B.B.D.J. was supported by a Marie Curie Fellowship (EEC grant MRTN-CT-2003-503618), as well as by the Association de la Recherche Contre le Cancer.

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