Redox Signaling by the RNA Polymerase III TFIIB-Related Factor Brf2.
Redox Signaling by the RNA Polymerase III TFIIB-Related Factor Brf2.
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DOI：
10.1016/j.cell.2015.11.005
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发表时间：
2015-12-03
期刊：
影响因子：
64.5
通讯作者：
Vannini A
中科院分区：
文献类型：
--
作者：
Gouge J;Satia K;Guthertz N;Widya M;Thompson AJ;Cousin P;Dergai O;Hernandez N;Vannini A
tfiib相关因子2 （Brf2）是tfiib样核心转录因子家族的成员。Brf2招募RNA聚合酶（Pol） III到III型基因-外部启动子，包括U6剪接体RNA和硒代半胱氨酸tRNA基因。仅在脊椎动物中发现，Brf2与肿瘤发生有关，但其潜在机制尚不清楚。我们已经解决了与天然启动子结合的人类Brf2-TBP复合物的晶体结构，获得了在brf2依赖的Pol III启动子上发生的分子相互作用的详细视图，并强调了人类Pol II和Pol III预起始复合物的一般结构和功能守恒。令人惊讶的是，我们的结构和功能研究揭示了Brf2氧化还原传感模块能够特异性调节活细胞中的Pol III转录输出。此外，我们建立了Brf2作为氧化应激途径的中心氧化还原感应转录因子，并提供了Brf2基因在肺癌和乳腺癌中激活的机制模型。TFIIB和TFIIB相关因子Brf2是氧化还原感应RNA聚合酶III核心转录因子Brf2调控细胞对氧化应激的反应，Brf2扩增使癌细胞逃避氧化应激诱导的凋亡，通过RNA聚合酶III核心转录因子Brf2直接感应氧化还原，将细胞对氧化应激的反应和转录输出的调控结合起来。有助于癌细胞逃避活性氧诱导的死亡。
TFIIB-related factor 2 (Brf2) is a member of the family of TFIIB-like core transcription factors. Brf2 recruits RNA polymerase (Pol) III to type III gene-external promoters, including the U6 spliceosomal RNA and selenocysteine tRNA genes. Found only in vertebrates, Brf2 has been linked to tumorigenesis but the underlying mechanisms remain elusive. We have solved crystal structures of a human Brf2-TBP complex bound to natural promoters, obtaining a detailed view of the molecular interactions occurring at Brf2-dependent Pol III promoters and highlighting the general structural and functional conservation of human Pol II and Pol III pre-initiation complexes. Surprisingly, our structural and functional studies unravel a Brf2 redox-sensing module capable of specifically regulating Pol III transcriptional output in living cells. Furthermore, we establish Brf2 as a central redox-sensing transcription factor involved in the oxidative stress pathway and provide a mechanistic model for Brf2 genetic activation in lung and breast cancer. Architectural conservation of TFIIB and TFIIB-related factors Brf2 is a redox-sensing RNA polymerase III core transcription factor Brf2 regulates cellular responses to oxidative stress Brf2 amplification enables cancer cells to evade oxidative stress-induced apoptosis Direct redox-sensing by the RNA polymerase III core transcription factor Brf2 couples cellular responses to oxidative stress and regulation of transcriptional output, contributing to the ability of cancer cells to evade death induced by reactive oxygen species.