1. Howard Hughes Medical Institute,
2. Molecular Pathology Graduate Program,
3. Department of Cellular and Molecular Medicine, and,
4. Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
5. Division of Gene Structure and Function, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama-Ken, Mail code 350-1241, Japan
6. Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
7. These authors contributed equally to this work.

Correspondence to: Michael G. Rosenfeld^1,4Christopher K. Glass^3,4Riki Kurokawa⁵ Correspondence and requests for materials should be addressed to R.K. (Email: rkurokaw@saitama-med.ac.jp), C.K.G. (Email: ckg@ucsd.edu) or M.G.R. (Email: mgr@ucsd.edu).

With the recent recognition of non-coding RNAs (ncRNAs) flanking many genes^{1, 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 mechanisms^{6, 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.

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