Induced ncRNAs Allosterically Modify RNA Binding Proteins in cis to Inhibit Transcription

By Xiangting Wang, S. Arai, Xiaoyuan Song, D. Reichart, K. Du, G. Pascual, Paul Tempst, M. Rosenfeld, Christopher K. Glass, R. Kurokawa. Nature, 2008

1,003 citations recorded by the source corpus.

With the recent recognition of non-coding RNAs (ncRNAs) flanking many genes, a central issue is to obtain a full understanding of their potential roles in regulated gene transcription programmes, possibly through different mechanisms. 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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fd0df2a85e6d3687e3df7d436f793342be63c54a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

Citations in the corpus

Mechanisms Underlying Inflammation in Neurodegeneration (2010, neutral): “The wild-type FUS/TLS protein contains RNA-binding motifs and is believed to be involved in transcriptional regulation (Uranishi et al., 2001; Wang et al., 2008).”
Evolution and functions of long noncoding RNAs. (2009, background): “…noncoding RNAs bind to an RNA-binding protein TLS (translocated in liposarcoma), thereby permitting, via an allosteric effect, interactions with histone acetyltransferases; the resultant inhibition of these acetyltransferases causes decreased CCND1 transcription (Wang et al., 2008) (Figure 4D).”
A Large Fraction of Extragenic RNA Pol II Transcription Sites Overlap Enhancers (2010, background): “For instance, nascent ncRNAs were shown to act as platforms for the recruitment of an RNA-binding transcriptional regulator upstream of the CCND1 gene [20], and the Evf2 ncRNA (derived from an ultraconserved regulatory region) was shown to act in trans to coactivate the homeodomain TF Dlx-2 [12].”
Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB (2013, background): “Similarly, an lncRNA transcribed from the 59regula- tory region of Cyclin D1 (CCND1) recruits TLS, an RNA-binding protein, to the CCND1 gene in response to DNA damage, and results in the transcription repression of CCND1 [33].”
Long non-coding RNAs: insights into functions (2009, background): “Proximal promoters can be transcribed into long ncRNAs that recruit and integrate the functions of RNA binding proteins into the transcriptional programme, as exemplified by the repression of cyclin D1 transcription in human cell line”
A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. (2015, neutral): “It is enriched in the nucleus and involved in transcription, DNA repair, and RNA biogenesis (Polymenidou et al., 2012; Wang et al., 2008, 2013).”