{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:28:07Z","timestamp":1790875687901,"version":"4.1.0"},"reference-count":56,"publisher":"Rockefeller University Press","issue":"13","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,12,21]]},"abstract":"<jats:p>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 \u201ccausative\u201d XPD point mutation R683W and different second mutant alleles, considered \u201cnull alleles.\u201d 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.<\/jats:p>","DOI":"10.1084\/jem.20091892","type":"journal-article","created":{"date-parts":[[2009,11,23]],"date-time":"2009-11-23T21:57:35Z","timestamp":1259013455000},"page":"3031-3046","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":50,"title":["Both\n                    <i>XPD<\/i>\n                    alleles contribute to the phenotype of compound heterozygote xeroderma pigmentosum patients"],"prefix":"10.1084","volume":"206","author":[{"given":"Takahiro","family":"Ueda","sequence":"first","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, BP 10142, 67404 Illkirch Cedex, C.U. Strasbourg, France 1"},{"name":"DNA Repair Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Compe","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, BP 10142, 67404 Illkirch Cedex, C.U. Strasbourg, France 1"},{"name":"Institut de Recherche sur les Cancers de l\u2019Appareil Digestif, F-67091 Strasbourg, France 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Catez","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, BP 10142, 67404 Illkirch Cedex, C.U. Strasbourg, France 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth H.","family":"Kraemer","sequence":"additional","affiliation":[{"name":"DNA Repair Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marc","family":"Egly","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, BP 10142, 67404 Illkirch Cedex, C.U. Strasbourg, France 1"},{"name":"Institut de Recherche sur les Cancers de l\u2019Appareil Digestif, F-67091 Strasbourg, France 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2009,11,23]]},"reference":[{"key":"2023072922513836800_bib1","doi-asserted-by":"publisher","first-page":"2233","DOI":"10.1210\/en.138.6.2233","article-title":"Mouse vitamin D-24-hydroxylase: molecular cloning, tissue distribution, and transcriptional regulation by 1alpha,25-dihydroxyvitamin D3","volume":"138","author":"Akeno","year":"1997","journal-title":"Endocrinology."},{"key":"2023072922513836800_bib2","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/377557a0","article-title":"Requirement for TFIIH kinase activity in transcription by RNA polymerase II","volume":"377","author":"Akoulitchev","year":"1995","journal-title":"Nature."},{"key":"2023072922513836800_bib3","doi-asserted-by":"publisher","first-page":"e322","DOI":"10.1371\/journal.pbio.0040322","article-title":"Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles","volume":"4","author":"Andressoo","year":"2006","journal-title":"PLoS Biol."},{"key":"2023072922513836800_bib4","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1101\/gad.14.3.349","article-title":"Nucleotide excision repair of DNA with recombinant human proteins: definition of the minimal set of factors, active forms of TFIIH, and modulation by CAK","volume":"14","author":"Ara\u00fajo","year":"2000","journal-title":"Genes Dev."},{"key":"2023072922513836800_bib5","doi-asserted-by":"publisher","first-page":"2919","DOI":"10.1093\/hmg\/11.23.2919","article-title":"Reduced level of the repair\/transcription factor TFIIH in trichothiodystrophy","volume":"11","author":"Botta","year":"2002","journal-title":"Hum. 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