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¹ Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 10142, 67404 Illkirch Cedex, C.U. Strasbourg, France
² DNA Repair Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889
³ Institut de Recherche sur les Cancers de l’Appareil Digestif, F-67091 Strasbourg, France

CORRESPONDENCE Jean-Marc Egly: egly{at}igbmc.fr

Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in the rare recessive genetic disorder xeroderma pigmentosum (XP). Many XP patients are compound heterozygotes with a "causative" XPD point mutation R683W and different second mutant alleles, considered "null alleles." However, there is marked clinical heterogeneity (including presence or absence of skin cancers or neurological degeneration) in these XPD/R683W patients, thus suggesting a contribution of the second allele. Here, we report XP patients carrying XPD/R683W and a second XPD allele either XPD/Q452X, /I455del, or /199insPP. We performed a systematic study of the effect of these XPD mutations on several enzymatic functions of TFIIH and found that each mutation exhibited unique biochemical properties. Although all the mutations inhibited the nucleotide excision repair (NER) by disturbing the XPD helicase function, each of them disrupted specific molecular steps during transcription: XPD/Q452X hindered the transactivation process, XPD/I455del disturbed RNA polymerase II phosphorylation, and XPD/199insPP inhibited kinase activity of the cdk7 subunit of TFIIH. The broad range and severity of clinical features in XP patients arise from a broad set of deficiencies in NER and transcription that result from the combination of mutations found on both XPD alleles.

T. Ueda's present address is Pharmaceuticals & Medical Devices Agency, Tokyo, Japan.

Abbreviations used: ChIP, chromatin immunoprecipitation; CTD, C-terminal domain; NER, nucleotide excision repair; TR, thyroid hormone receptor; TRE, thyroid hormone response element; TTD, trichothiodystrophy; XP, xeroderma pigmentosum; XPD, xeroderma pigmentosum group D gene.

© 2009 Ueda et al.
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This article has been cited by other articles:

• Ueda, T., Compe, E., Catez, P., Kraemer, K. H., Egly, J.-M. (2009). Both XPD alleles contribute to the phenotype of compound heterozygote xeroderma pigmentosum patients. JCB 187: i13-i13 [Full Text]  

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