Basal transcription defect discriminates between xeroderma pigmentosum and trichothiodystrophy in XPD patients
Basal transcription defect discriminates between xeroderma pigmentosum and trichothiodystrophy in XPD patients
复制标题
DOI：
10.1016/s1097-2765(03)00182-5
复制
发表时间：
2003-06-01
期刊：
影响因子：
16
通讯作者：
Egly, JM
中科院分区：
文献类型：
--
作者：
Dubaele, S;De Santis, LP;Egly, JM
XPD基因突变导致色素性干皮病(XP)和毛发硫代营养不良(TTD)，其表型往往错综复杂。为了了解基因型/表型的关系，我们设计了重组TFIIH，其中XPD亚基携带在XPD患者中发现的氨基酸变化。我们证明了所有XPD突变都对XPD解旋酶活性有害，从而解释了NER缺陷。我们还表明，来自TTD患者的TFIIH，而不是来自XP患者的TFIIH，除了细胞内浓度降低外，还显示出显著的体外基础转录缺陷。此外，当XPD突变阻止与TFIIH的p44亚单位相互作用时，某些核受体指导的反式激活被抑制，而无论TTD和XP的表型如何，从而解释了重叠的症状。使用XPD蛋白的结构模型讨论了这些突变的含义。我们的研究为各种临床特征的性质和严重性提供了解释。
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.