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

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Abstract
DNA damage induces expression of a non-coding RNA, which acts like a ligand to recruit a specific RNA-binding protein, TLS. This protein in turn represses transcription of the gene to which the non-coding RNA is tethered by inhibiting a histone acetyltransferase coactivator. These data suggest that non-coding RNAs induced in regulatory regions of transcription units recruit and modulate the activities of distinct classes of RNA binding co-regulators in response to specific signalling programs, providing an unexpected RNA-based strategy to integrate transcriptional programs. A signal-induced non-coding RNA is shown to act like a ligand to activate a specific RNA-binding protein, TLS. This protein in turn represses gene transcription by inhibiting a histone acetyltransferase coactivator. 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.