Distinct roles for the XPB/p52 and XPD/p44 subcomplexes of TFIIH in damaged DNA opening during nucleotide excision repair
Distinct roles for the XPB/p52 and XPD/p44 subcomplexes of TFIIH in damaged DNA opening during nucleotide excision repair
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DOI：
10.1016/j.molcel.2007.03.009
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发表时间：
2007-04-27
期刊：
影响因子：
16
通讯作者：
Egly, Jean-Marc
中科院分区：
文献类型：
--
作者：
Coin, Frederic;Oksenych, Valentyn;Egly, Jean-Marc
XPB是转录/修复因子TFIIH的重要亚基，其突变可导致核苷酸切除修复（NER）缺陷和干皮病。萎缩(XP)。XPB在NER中的作用以及导致XP的分子机制尚不清楚。在这里，我们发现TFIIH的p52亚基与XPB相互作用并刺激其atp酶活性。在XP-B患者（F99S）中发现的突变削弱了这种相互作用和由此产生的atp酶刺激，从而解释了受损DNA开口的缺陷。接下来，我们发现抑制XPB解旋酶活性的解旋酶基序III （T469A）和VI （Q638A）的突变保留了TFIIH的NER功能。我们的研究结果表明，XPB的解旋酶活性不是用于打开和修复受损DNA的机制，而是仅由其atp酶活性和XPD的解旋酶活性共同驱动。
Mutations in XPB, an essential subunit of the transcription/repair factor TFIIH, lead to nucleotide excision repair (NER) defects and xeroderma. pigmentosum (XP). The role of XPB in NER and the molecular mechanisms resulting in XP are poorly understood. Here, we show that the p52 subunit of TFIIH interacts with XPB and stimulates its ATPase activity. A mutation found among XP-B patients (F99S) weakens this interaction and the resulting ATPase stimulation, thereby explaining the defect in the damaged DNA opening. We next found that mutations in the helicase motifs III (T469A) and VI (Q638A) that inhibit XPB helicase activity preserve the NER function of TFIIH. Our results suggest a mechanism in which the helicase activity of XPB is not used for the opening and repair of damaged DNA, which is instead only driven by its ATPase activity, in combination with the helicase activity of XPD.