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Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription

Abstract

With the recent recognition of non-coding RNAs (ncRNAs) flanking many genes1,2,3,4,5, a central issue is to obtain a full understanding of their potential roles in regulated gene transcription programmes, possibly through different mechanisms6,7,8,9,10,11,12. Here we show that an RNA-binding protein, TLS (for translocated in liposarcoma), serves as a key transcriptional regulatory sensor of DNA damage signals that, on the basis of its allosteric modulation by RNA, specifically binds to and inhibits CREB-binding protein (CBP) and p300 histone acetyltransferase activities on a repressed gene target, cyclin D1 (CCND1) in human cell lines. 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 programmes.

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Figure 1: TLS is a specific inhibitor of CBP and p300 HAT activity.
Figure 2: Consensus GGUG-containing RNA oligonucleotide promotes the inhibitory effect of TLS on CBP and p300 HAT activities.
Figure 3: TLS negatively regulates the CBP and p300 HAT-regulated CCND1 gene.
Figure 4: ncRNA CCND1 s are predominantly single-stranded, DNA-bound species that bind to TLS.
Figure 5: ncRNA CCND1 negatively regulates CCND1 transcription by recruiting TLS to the CCND1 promoter.

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Acknowledgements

We thank A. Gettings for help with mass spectrometric analysis; M. Hiramatsu, W. Sato and C. Nelson for technical assistance; A. Matsushita, M. Matsubara and T. Oyoshi for discussion; and J. Hightower and M. Fisher for figure and manuscript preparation. This work was supported by the Fujisawa Foundation, the Takeda Science Foundation, the Naito Foundation, Sankyo Foundation Life Science, and grants-in-aid (nos 17054036 and 18055029) from the Ministry of Education, Culture, Sports, Science, and Technology in Japan to R.K., by National Institutes of Health grants CA52599 and HL59694 to C.K.G., by National Cancer Institute Cancer Center Support grant P30 CA08748 to P.T., by NS34934, DK39949 and CA097134 to M.G.R., and by DK074868 to C.K.G. and M.G.R. M.G.R. is a Howard Hughes Medical Institute investigator.

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Correspondence to Michael G. Rosenfeld, Christopher K. Glass or Riki Kurokawa.

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Wang, X., Arai, S., Song, X. et al. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454, 126–130 (2008). https://doi.org/10.1038/nature06992

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