Here we identify PURB, a dual DNA/RNA-binding protein, as a key mediator for LncRNAs to interact with p53. PURB is overexpressed in human cancers and loss of PURB expression in human cancer cells induces tumor growth suppression by activating p53. Interestingly, PURB knockdown activates only a subset of p53 target genes without affecting p53 protein levels and PURB is specifically recruited by p53 to the target genes in a promoter-specific manner. Moreover, a unique cis-regulatory element is identified at the target promoters recognized by PURB; loss of this element does not affect p53-mediated transactivation but abrogates the ability of p53 to recruit PURB to the promoters for repression. Notably, the ability of PURB in transcriptional repression requires its sequence-specific binding with HOTAIR, one of LncRNAs tightly associated with PURB. HOTAIR interacts directly with SUV39H1 and, bridging by the PURB/HOTAIR complex, p53 is able to recruit SUV39H1 histone methyltransferase to the target promoters for transcriptional repression. These data establish a new mode of LncRNA-mediated regulation of p53 transcription in a sequence-specific manner and also reveal, a previously unanticipated mechanism for promoter-specific regulation through a unique cis-regulatory element recognized by the LncRNA-protein complex.