Dubaele Sandy, Proietti De Santis Luca, Bienstock Rachelle J, Keriel Anne, Stefanini Miria, Van Houten Bennett, Egly Jean-Marc
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 10142, 67404 Illkirch Cedex, C.U. Strasbourg, France.
Mol Cell. 2003 Jun;11(6):1635-46. doi: 10.1016/s1097-2765(03)00182-5.
Mutations in the XPD gene result in xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), the phenotypes of which are often intricate. To understand the genotype/phenotype relationship, we engineered recombinant TFIIHs in which XPD subunits carry amino acid changes found in XPD patients. We demonstrate that all the XPD mutations are detrimental for XPD helicase activity, thus explaining the NER defect. We also show that TFIIH from TTD patients, but not from XP patients, exhibits a significant in vitro basal transcription defect in addition to a reduced intracellular concentration. Moreover, when XPD mutations prevent interaction with the p44 subunit of TFIIH, transactivation directed by certain nuclear receptors is inhibited, regardless of TTD versus XP phenotype, thus explaining the overlapping symptoms. The implications of these mutations are discussed using a structural model of the XPD protein. Our study provides explanations for the nature and the severity of the various clinical features.
XPD基因的突变会导致着色性干皮病（XP）和毛发硫营养不良（TTD），其表型往往错综复杂。为了理解基因型/表型关系，我们构建了重组TFIIHs，其中XPD亚基带有在XPD患者中发现的氨基酸变化。我们证明所有XPD突变均对XPD解旋酶活性有害，从而解释了核苷酸切除修复（NER）缺陷。我们还表明，来自TTD患者而非XP患者的TFIIH除细胞内浓度降低外，在体外还表现出明显的基础转录缺陷。此外，当XPD突变阻止与TFIIH的p44亚基相互作用时，无论TTD还是XP表型，某些核受体介导的反式激活都会受到抑制，从而解释了重叠症状。使用XPD蛋白的结构模型讨论了这些突变的影响。我们的研究为各种临床特征的性质和严重程度提供了解释。
