UC San Diego

A large number of coactivators and corepressors are required for regulating programs of gene expression in a transcription factor- and gene-specific manner, suggesting that they serve as both sensors and integrators of signaling information to coordinate complex homeostatic responses. A central emerging goal in gene regulation is to fully understand the roles of previously unrecognized non-coding RNAs in regulated gene transcription programs. Here, we report that the RNA-binding protein, TLS, serves as a key transcriptional regulatory sensor of DNA damage signals by specifically binding to and allosterically inhibiting CBP/p300 HAT activities on repressed gene targets. Recruitment of TLS to the CCND1 promoter and gene -specific repression are directed by non-coding RNA transcripts from the 5' regulatory regions of CCND1, acting as molecular beacons that are themselves induced in response to DNA damage signals. These data suggest that non-coding RNAs induced in regulatory regions of transcription units may act as selective ligands, recruiting and modulating the activities of distinct classes of RNA binding co-regulators in response to specific signaling programs, providing an unexpected RNA- based strategy to integrate transcriptional programs