Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription.
Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription.
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DOI：
10.1038/nature06992
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发表时间：
2008-07-03
期刊：
影响因子：
64.8
通讯作者：
Kurokawa, Riki
中科院分区：
文献类型：
--
作者：
Wang, Xiangting;Arai, Shigeki;Song, Xiaoyuan;Reichart, Donna;Du, Kun;Pascual, Gabriel;Tempst, Paul;Rosenfeld, Michael G.;Glass, Christopher K.;Kurokawa, Riki
随着最近对许多基因侧翼的非编码RNA（ncRNA）的认识，一个中心问题是充分理解它们在调控基因转录程序中的潜在作用，可能通过不同的机制。在这里，我们报告说，RNA结合蛋白，TLS，作为一个关键的转录调控传感器的DNA损伤信号，基于其变构调制的RNA，特异性结合并抑制CBP/p300 HAT活动的抑制基因靶点，细胞周期蛋白D1（CCND 1）。TLS向CCND 1启动子的募集以引起基因特异性抑制是由单链、低拷贝数ncRNA转录物指导的，所述转录物系于CCND 1的5′调控区，其响应于DNA损伤信号而被诱导。我们的数据表明，信号诱导的ncRNA定位到转录单位的调控区域可以协同作为选择性配体，招募和调节不同类别的RNA结合辅助调节因子的活动，以响应特定的信号，提供了一个意想不到的ncRNA/RNA结合蛋白为基础的策略，整合转录程序。
With the recent recognition of non-coding RNAs (ncRNAs) flanking many genes, a central issue is to fully understand their potential roles in regulated gene transcription programs, possibly through different mechanisms. Here, we report that an RNA-binding protein, TLS, serves as a key transcriptional regulatory sensor of DNA damage signals that, based on its allosteric modulation by RNA, specifically binds to and inhibits CBP/p300 HAT activities on a repressed gene target, cyclin D1 (CCND1). Recruitment of TLS to the CCND1 promoter to cause gene-specific repression is directed by single stranded, low copy number ncRNA transcripts tethered to the 5′ regulatory regions of CCND1 that are induced in response to DNA damage signals. Our data suggest that signal-induced ncRNAs localized to regulatory regions of transcription units can act cooperatively as selective ligands, recruiting and modulating the activities of distinct classes of RNA binding co-regulators in response to specific signals, providing an unexpected ncRNA/RNA-binding protein-based strategy to integrate transcriptional programs.
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