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The PURB-HOTAIR complex regulates p53-dependent promoter-specific transcriptional activation [RNA-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: GSE295588 | GEO | 2025/04/24

REPOSITORIES: GEO

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

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

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