This study investigates the role of non-coding RNAs (ncRNAs) in regulating gene transcription, specifically focusing on the interaction between an RNA-binding protein, TLS, and histone acetyltransferases (HATs) CBP and p300. TLS is identified as a key sensor of DNA damage signals, which, through allosteric modulation by RNA, specifically binds to and inhibits the HAT activities of CBP and p300 on the repressed gene target, cyclin D1 (CCND1). The recruitment of TLS to the CCND1 promoter is directed by single-stranded, low-copy number ncRNA transcripts that are induced in response to DNA damage signals. These ncRNAs act as selective ligands, recruiting and modulating the activities of distinct classes of RNA binding co-regulators, providing a novel strategy for integrating transcriptional programs. The study also demonstrates that ncRNAs can serve as molecular "ligands" for specific RNA binding proteins, causing allosteric effects that release the proteins from an inactive conformation, allowing them to interact with target proteins and regulate gene expression.This study investigates the role of non-coding RNAs (ncRNAs) in regulating gene transcription, specifically focusing on the interaction between an RNA-binding protein, TLS, and histone acetyltransferases (HATs) CBP and p300. TLS is identified as a key sensor of DNA damage signals, which, through allosteric modulation by RNA, specifically binds to and inhibits the HAT activities of CBP and p300 on the repressed gene target, cyclin D1 (CCND1). The recruitment of TLS to the CCND1 promoter is directed by single-stranded, low-copy number ncRNA transcripts that are induced in response to DNA damage signals. These ncRNAs act as selective ligands, recruiting and modulating the activities of distinct classes of RNA binding co-regulators, providing a novel strategy for integrating transcriptional programs. The study also demonstrates that ncRNAs can serve as molecular "ligands" for specific RNA binding proteins, causing allosteric effects that release the proteins from an inactive conformation, allowing them to interact with target proteins and regulate gene expression.