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

Nature. 2008 Jul 3;454(7200):126-30. doi: 10.1038/nature06992. Epub 2008 May 28.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation
  • CREB-Binding Protein / antagonists & inhibitors
  • CREB-Binding Protein / metabolism
  • Cell Line
  • Consensus Sequence
  • Cyclin D1 / genetics
  • DNA Damage
  • Down-Regulation*
  • HeLa Cells
  • Histone Acetyltransferases / antagonists & inhibitors
  • Histone Acetyltransferases / metabolism
  • Humans
  • Oligonucleotides / genetics
  • Promoter Regions, Genetic / genetics
  • RNA, Untranslated / genetics
  • RNA, Untranslated / metabolism*
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / metabolism*
  • Transcription, Genetic*

Substances

  • Oligonucleotides
  • RNA, Untranslated
  • RNA-Binding Protein FUS
  • Cyclin D1
  • CREB-Binding Protein
  • Histone Acetyltransferases