ARCH domain of XPD, an anchoring platform for CAK that conditions TFIIH DNA repair and transcription activities
ARCH domain of XPD, an anchoring platform for CAK that conditions TFIIH DNA repair and transcription activities
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DOI：
10.1073/pnas.1213981110
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发表时间：
2013-02-19
影响因子：
11.1
通讯作者：
Poterszman, Arnaud
中科院分区：
文献类型：
--
作者：
Abdulrahman, Wassim;Iltis, Izarn;Poterszman, Arnaud
着色性干皮病D组（XPD）解旋酶是转录/DNA修复因子、转录因子II H（TFIIH）的亚基，其在核苷酸切除修复期间催化受损DNA双链体的解旋。除了两个典型的解旋酶结构域外，XPD还包括一个参与DNA损伤识别的4Fe-S簇结构域和一个被称为“解旋结构域”的未表征功能模块。“通过研究在一名患有硫代谢障碍的患者中发现的突变的后果，我们表明，CDK结构域对于细胞周期蛋白依赖性激酶（CDK）-激活激酶（CAK）复合物的募集至关重要。事实上，这种突变不仅影响与MAT 1 CAK亚基的相互作用，从而降低TFIIH本身的体外基础转录活性并阻碍转录机制在活化基因的启动子上的有效募集，而且还损害XPD的DNA解旋活性和TFIIH的核苷酸切除修复活性。我们进一步证明了CAK在下调TFIIH内XPD解旋酶活性中的作用。两者合计，我们的研究结果确定XPD作为CAK的招聘平台，并作为一个潜在的分子开关，可能会控制TFIIH组合物，并发挥关键作用，在TFIIH从转录活跃的因子转换为参与DNA修复的因子。
The xeroderma pigmentosum group D (XPD) helicase is a subunit of transcription/DNA repair factor, transcription factor II H (TFIIH) that catalyzes the unwinding of a damaged DNA duplex during nucleotide excision repair. Apart from two canonical helicase domains, XPD is composed of a 4Fe-S cluster domain involved in DNA damage recognition and a module of uncharacterized function termed the "ARCH domain." By investigating the consequences of a mutation found in a patient with trichothiodystrophy, we show that the ARCH domain is critical for the recruitment of the cyclin-dependent kinase (CDK)-activating kinase (CAK) complex. Indeed, this mutation not only affects the interaction with the MAT1 CAK subunit, thereby decreasing the in vitro basal transcription activity of TFIIH itself and impeding the efficient recruitment of the transcription machinery on the promoter of an activated gene, but also impairs the DNA unwinding activity of XPD and the nucleotide excision repair activity of TFIIH. We further demonstrate the role of CAK in downregulating the XPD helicase activity within TFIIH. Taken together, our results identify the ARCH domain of XPD as a platform for the recruitment of CAK and as a potential molecular switch that might control TFIIH composition and play a key role in the conversion of TFIIH from a factor active in transcription to a factor involved in DNA repair.