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首页> 外文期刊>Molecular and Cellular Biology >DNA Repair and Transcriptional Deficiencies Caused by Mutations in the Drosophila p52 Subunit of TFIIH Generate Developmental Defects and Chromosome Fragility
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DNA Repair and Transcriptional Deficiencies Caused by Mutations in the Drosophila p52 Subunit of TFIIH Generate Developmental Defects and Chromosome Fragility

机译：果蝇p52亚基​​的果蝇p52亚基​​突变引起的DNA修复和转录缺陷产生发育缺陷和染色体易碎性。

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摘要

The transcription and DNA repair factor TFIIH is composed of 10 subunits. Mutations in the XPB, XPD, and p8 subunits are genetically linked to human diseases, including cancer. However, no reports of mutations in other TFIIH subunits have been reported in higher eukaryotes. Here, we analyze at genetic, molecular, and biochemical levels the Drosophila melanogaster p52 (DMP52) subunit of TFIIH. We found that DMP52 is encoded by the gene marionette in Drosophila and that a defective DMP52 produces UV light-sensitive flies and specific phenotypes during development: organisms are smaller than their wild-type siblings and present tumors and chromosomal instability. The human homologue of DMP52 partially rescues some of these phenotypes. Some of the defects observed in the fly caused by mutations in DMP52 generate trichothiodystrophy and cancer-like phenotypes. Biochemical analysis of DMP52 point mutations introduced in human p52 at positions homologous to those of defects in DMP52 destabilize the interaction between p52 and XPB, another TFIIH subunit, thus compromising the assembly of the complex. This study significantly extends the role of p52 in regulating XPB ATPase activity and, consequently, both its transcriptional and nucleotide excision repair functions.
机译：转录和DNA修复因子TFIIH由10个亚基组成。 XPB，XPD和p8亚基中的突变与包括癌症在内的人类疾病具有遗传联系。但是，在高等真核生物中，尚无其他TFIIH亚基突变的报道。在这里，我们在遗传，分子和生化水平上分析了TFIIH的果蝇（Drosophila melanogaster） p52（DMP52）亚基。我们发现DMP52由果蝇（ems果蝇）中的 marionette 基因编码，有缺陷的DMP52在发育过程中会产生对紫外线敏感的果蝇和特定的表型：生物体比野生型小类型的兄弟姐妹和目前的肿瘤和染色体不稳定。 DMP52的人类同源物部分拯救了其中一些表型。 DMP52突变引起的在飞行中观察到的一些缺陷会产生毛发硫代营养不良和癌症样表型。对人p52中与DMP52缺陷缺陷同源的位置中引入的DMP52点突变的生化分析破坏了p52和XPB（另一个TFIIH亚基）之间的相互作用的稳定性，从而损害了复合物的组装。这项研究显着扩展了p52在调节XPB ATPase活性中的作用，并因此扩展了其转录和核苷酸切除修复功能。

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