Induced non-coding RNAs (ncRNAs) allosterically modify RNA-binding proteins in cis to inhibit transcription. This study shows that the RNA-binding protein TLS acts as a key transcriptional regulatory sensor of DNA damage signals. TLS specifically binds to and inhibits CBP/p300 histone acetyltransferase (HAT) activities on the repressed gene target cyclin D1 (CCND1). TLS recruitment to the CCND1 promoter is directed by single-stranded, low copy number ncRNA transcripts tethered to the 5' regulatory regions of CCND1, which are induced in response to DNA damage signals. These ncRNAs 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 ncRNA/RNA-binding protein-based strategy to integrate transcriptional programs. Transcriptional co-regulators, including coactivators and corepressors, are essential for regulating gene expression in a transcription factor- and gene-specific manner. CBP and p300, histone acetyltransferases, play essential roles as coactivators of multiple classes of signal-dependent transcription factors. The study found that TLS inhibits CBP HAT activity on histones, and this inhibition is RNA-dependent. TLS interacts with specific ncRNAs, which are induced in response to DNA damage signals. These ncRNAs are predominantly single-stranded and DNA-bound, and they bind to TLS, allowing TLS to interact with CBP/p300 and allosterically regulate HAT activity. The study also shows that TLS negatively regulates the CBP/p300 HAT-regulated CCND1 gene. CCND1 is a cell cycle regulator repressed by DNA damage signals and is an endogenous CREB target gene. TLS interacts with ncRNAs that are induced in response to DNA damage signals, and this interaction leads to the repression of CCND1 transcription. The study further demonstrates that ncRNAs can act as molecular "ligands" for TLS, causing an allosteric effect that releases TLS from an inactive conformation, allowing gene-specific TLS:CBP/p300 interactions that inhibit CBP/p300 HAT functions and repression of transcription. The findings suggest that ncRNAs can regulate gene expression by recruiting and modulating the activities of RNA-binding co-regulators in response to specific signals.Induced non-coding RNAs (ncRNAs) allosterically modify RNA-binding proteins in cis to inhibit transcription. This study shows that the RNA-binding protein TLS acts as a key transcriptional regulatory sensor of DNA damage signals. TLS specifically binds to and inhibits CBP/p300 histone acetyltransferase (HAT) activities on the repressed gene target cyclin D1 (CCND1). TLS recruitment to the CCND1 promoter is directed by single-stranded, low copy number ncRNA transcripts tethered to the 5' regulatory regions of CCND1, which are induced in response to DNA damage signals. These ncRNAs 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 ncRNA/RNA-binding protein-based strategy to integrate transcriptional programs. Transcriptional co-regulators, including coactivators and corepressors, are essential for regulating gene expression in a transcription factor- and gene-specific manner. CBP and p300, histone acetyltransferases, play essential roles as coactivators of multiple classes of signal-dependent transcription factors. The study found that TLS inhibits CBP HAT activity on histones, and this inhibition is RNA-dependent. TLS interacts with specific ncRNAs, which are induced in response to DNA damage signals. These ncRNAs are predominantly single-stranded and DNA-bound, and they bind to TLS, allowing TLS to interact with CBP/p300 and allosterically regulate HAT activity. The study also shows that TLS negatively regulates the CBP/p300 HAT-regulated CCND1 gene. CCND1 is a cell cycle regulator repressed by DNA damage signals and is an endogenous CREB target gene. TLS interacts with ncRNAs that are induced in response to DNA damage signals, and this interaction leads to the repression of CCND1 transcription. The study further demonstrates that ncRNAs can act as molecular "ligands" for TLS, causing an allosteric effect that releases TLS from an inactive conformation, allowing gene-specific TLS:CBP/p300 interactions that inhibit CBP/p300 HAT functions and repression of transcription. The findings suggest that ncRNAs can regulate gene expression by recruiting and modulating the activities of RNA-binding co-regulators in response to specific signals.