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

With the recent recognition of non- coding RNAs ( ncRNAs) flanking many genes(1-5), a central issue is to obtain a full understanding of their potential roles in regulated gene transcription programmes, possibly through different mechanisms(6-12). 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.