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


Authors: Wang, X.; Arai, S.; Song, X.; Reichart, D.; Du, K.; Pascual, G.; Tempst, P.; Rosenfeld, M. G.; Glass, C. K.; Kurokawa, R.
Article Title: Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription
Abstract: 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. ©2008 Macmillan Publishers Limited. All rights reserved.
Keywords: signal transduction; controlled study; human cell; dna damage; gene targeting; cell line; protein; down-regulation; genetic transcription; protein interaction; transcription, genetic; enzyme activity; hela cells; rna binding protein; rna; dna; gene repression; dna flanking region; rna, untranslated; cyclin d1; rna binding; gene location; protein modification; oligonucleotides; cyclic amp responsive element binding protein; allosteric regulation; allosterism; inhibition; rna-binding protein fus; protein p300; consensus sequence; single stranded rna; promoter regions (genetics); histone acetyltransferase; 3 (3 cyclopentyloxy 4 methoxybenzyl) 6 ethylamino 8 isopropyl 3h purine; protein tls; creb-binding protein; histone acetyltransferases
Journal Title: Nature
Volume: 454
Issue: 7200
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2008-07-03
Start Page: 126
End Page: 130
Language: English
DOI: 10.1038/nature06992
PUBMED: 18509338
PROVIDER: scopus
PMCID: PMC2823488
DOI/URL:
Notes: --- - "Cited By (since 1996): 132" - "Export Date: 17 November 2011" - "CODEN: NATUA" - "Source: Scopus"
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Paul J Tempst
    324 Tempst