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The PURB-HOTAIR complex regulates p53-dependent promoter-specific transcriptional activation [CLIP-Seq]

ABSTRACT: p53 executes its diverse functions via different transcriptional targets, but the precise mechanism of promoter-specific regulation by p53 remains largely unknown. Through biochemical purification, we identify PURB, a dual DNA/RNA-binding protein, that acts as a transcriptional co-repressor for p53 in a manner dependent on p53 acetylation status. PURB is overexpressed in human cancers while its knockdown induces p53-dependent activation of p21 but has no effect on other major promoters such as PUMA and Mdm2. In contrast to other p53 corepressors, PURB can recognize a unique DNA element at the p21 promoter, with the loss of this element not affecting p53-mediated transactivation but abrogating the ability of p53 to recruit PURB to the p21 promoter for repression. Mechanistically, PURB requires its sequence-specific binding with lncRNA HOTAIR to exert its repressive role. In turn, HOTAIR interacts directly with EZH2 and, bridged by the PURB/HOTAIR complex, p53 can recruit the EZH2 histone methyltransferase to target promoters for transcriptional repression. Further analysis of p53 targets indicates a number of promoters that may serve as a target for PURB-binding, suggesting that this mechanism of PURB-dependent promoter-specific regulation may not be limited to p21. These data establish a mode of LncRNA-mediated regulation of p53 transcription in a sequence-specific manner and reveal a previously unanticipated mechanism for acetylation-mediated promoter-specific regulation through a cis-regulatory element recognized by the PURB-HOTAIR complex.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295618 | GEO | 2025/04/25

REPOSITORIES: GEO

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The PURB-HOTAIR complex regulates p53-dependent promoter-specific transcriptional activation [RNA-Seq]

Project description:p53 executes its diverse functions via different transcriptional targets, but the precise mechanism of promoter-specific regulation by p53 remains largely unknown. Through biochemical purification, we identify PURB, a dual DNA/RNA-binding protein, that acts as a transcriptional co-repressor for p53 in a manner dependent on p53 acetylation status. PURB is overexpressed in human cancers while its knockdown induces p53-dependent activation of p21 but has no effect on other major promoters such as PUMA and Mdm2. In contrast to other p53 corepressors, PURB can recognize a unique DNA element at the p21 promoter, with the loss of this element not affecting p53-mediated transactivation but abrogating the ability of p53 to recruit PURB to the p21 promoter for repression. Mechanistically, PURB requires its sequence-specific binding with lncRNA HOTAIR to exert its repressive role. In turn, HOTAIR interacts directly with EZH2 and, bridged by the PURB/HOTAIR complex, p53 can recruit the EZH2 histone methyltransferase to target promoters for transcriptional repression. Further analysis of p53 targets indicates a number of promoters that may serve as a target for PURB-binding, suggesting that this mechanism of PURB-dependent promoter-specific regulation may not be limited to p21. These data establish a mode of LncRNA-mediated regulation of p53 transcription in a sequence-specific manner and reveal a previously unanticipated mechanism for acetylation-mediated promoter-specific regulation through a cis-regulatory element recognized by the PURB-HOTAIR complex.

2025-04-24 | GSE295588 | GEO

Sequence-specific binding between HOTAIR and PURB reveals a new mode for LncRNA-mediated regulation of p53

Project description: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.

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Project description:The PURB-HOTAIR complex regulates p53-dependent promoter-specific transcriptional activation

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