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Molecular and Cellular Biology, October 2007, p. 6606-6614, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.02166-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

In Vivo Destabilization and Functional Defects of the Xeroderma Pigmentosum C Protein Caused by a Pathogenic Missense Mutation ^,

Gentaro Yasuda,^1,2,3,4, Ryotaro Nishi,^1,2,3,4,6, Eriko Watanabe,¹ Toshio Mori,⁷ Shigenori Iwai,⁵ Donata Orioli,⁸ Miria Stefanini,⁸ Fumio Hanaoka,^1,2,4 and Kaoru Sugasawa^1,2,6*

Cellular Physiology Laboratory, RIKEN Discovery Research Institute,¹ SORST, Japan Science and Technology Agency, Saitama,² Graduate School of Pharmaceutical Sciences,³ Graduate School of Frontier Biosciences,⁴ Graduate School of Engineering Sciences, Osaka University, Osaka,⁵ Biosignal Research Center, Kobe University, Hyogo,⁶ Radioisotope Center, Nara Medical University, Nara, Japan,⁷ Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy⁸

Received 18 November 2006/ Returned for modification 26 December 2006/ Accepted 24 July 2007

Xeroderma pigmentosum group C (XPC) protein plays an essential role in DNA damage recognition in mammalian global genome nucleotide excision repair (NER). Here, we analyze the functional basis of NER inactivation caused by a single amino acid substitution (Trp to Ser at position 690) in XPC, previously identified in the XPC patient XP13PV. The Trp690Ser change dramatically affects the in vivo stability of the XPC protein, thereby causing a significant reduction of its steady-state level in XP13PV fibroblasts. Despite normal heterotrimeric complex formation and physical interactions with other NER factors, the mutant XPC protein lacks binding affinity for both undamaged and damaged DNA. Thus, this single amino acid substitution is sufficient to compromise XPC function through both quantitative and qualitative alterations of the protein. Although the mutant XPC fails to recognize damaged DNA, it is still capable of accumulating in a UV-damaged DNA-binding protein (UV-DDB)-dependent manner to UV-damaged subnuclear domains. However, the NER factors transcription factor IIH and XPA failed to colocalize stably with the mutant XPC. As well as highlighting the importance of UV-DDB in recruiting XPC to UV-damaged sites, these findings demonstrate the role of DNA binding by XPC in the assembly of subsequent NER intermediate complexes.

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* Corresponding author. Mailing address: Biosignal Research Center, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe, Hyogo 657-8501, Japan. Phone: 81 78 803 5960. Fax: 81 78 803 5970. E-mail: ksugasawa{at}garnet.kobe-u.ac.jp

Published ahead of print on 6 August 2007.

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

These two authors contributed equally to this work.

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Molecular and Cellular Biology, October 2007, p. 6606-6614, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.02166-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Bernardes de Jesus, B. M., Bjoras, M., Coin, F., Egly, J. M. (2008). Dissection of the Molecular Defects Caused by Pathogenic Mutations in the DNA Repair Factor XPC. Mol. Cell. Biol. 28: 7225-7235 [Abstract] [Full Text]