Tripartite DNA Lesion Recognition and Verification by XPC, TFIIH, and XPA in Nucleotide Excision Repair.
Tripartite DNA Lesion Recognition and Verification by XPC, TFIIH, and XPA in Nucleotide Excision Repair.
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DOI：
10.1016/j.molcel.2015.08.012
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发表时间：
2015-09-17
期刊：
影响因子：
16
通讯作者：
Yang W
中科院分区：
文献类型：
--
作者：
Li CL;Golebiowski FM;Onishi Y;Samara NL;Sugasawa K;Yang W
转录因子IIH（TFIIH）是转录和核苷酸切除修复（NER）所必需的。DNA病变最初检测到NER因子XPC和XPE或停滞的RNA聚合酶，但只有大的病变优先修复NER。为了阐明NER中的底物特异性，我们制备了不含CAK模块的均质人十亚基TFIIH及其七亚基核心（Core7），并表明DNA中的大体积病变抑制了Core7中XPB和XPD的ATP酶和解旋酶活性以促进NER，而非真正的NER底物则没有这种作用。此外，NER因子XPA通过Core7激活正常DNA的解旋，但在大体积病变存在下抑制Core7解旋酶活性。最后，CAK模块通过TFIIH抑制DNA结合，从而增强TFIIH的XPC依赖性特异性募集。我们的研究结果支持三方病变验证机制，涉及XPC，TFIIH，和XPA的有效NER。
Transcription factor IIH (TFIIH) is essential for both transcription and nucleotide excision repair (NER). DNA lesions are initially detected by NER factors XPC and XPE or stalled RNA polymerases, but only bulky lesions are preferentially repaired by NER. To elucidate substrate specificity in NER, we have prepared homogeneous human ten-subunit TFIIH and its seven-subunit core (Core7) without the CAK module and show that bulky lesions in DNA inhibit the ATPase and helicase activities of both XPB and XPD in Core7 to promote NER, whereas non-genuine NER substrates have no such effect. Moreover, the NER factor XPA activates unwinding of normal DNA by Core7, but inhibits the Core7 helicase activity in the presence of bulky lesions. Finally, the CAK module inhibits DNA binding by TFIIH and thereby enhances XPC-dependent specific recruitment of TFIIH. Our results support a tripartite lesion verification mechanism involving XPC, TFIIH, and XPA for efficient NER.