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

ABSTRACT: p53 executes its diverse functions through different transcriptional targets but the precise mechanism of promoter-specific regulation by p53 remains largely unknown. Through biochemical purification, we identify purine-rich element binding protein B (PURB), a dual DNA/RNA-binding protein, which acts as a transcriptional corepressor for p53 in a manner dependent on p53 acetylation status. PURB is overexpressed in human cancers, and 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 long noncoding RNA (lncRNA) HOX transcript antisense RNA (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 reveals several promoters that may serve as targets 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

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, which 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:p53 executes its diverse functions through different transcriptional targets but the precise mechanism of promoter-specific regulation by p53 remains largely unknown. Through biochemical purification, we identify purine-rich element binding protein B (PURB), a dual DNA/RNA-binding protein, which acts as a transcriptional corepressor for p53 in a manner dependent on p53 acetylation status. PURB is overexpressed in human cancers, and 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 long noncoding RNA (lncRNA) HOX transcript antisense RNA (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 reveals several promoters that may serve as targets 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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