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?Np63? represses anti-proliferative genes via H2A.Z deposition.


ABSTRACT: ?Np63? is a member of the p53 family of transcription factors that functions as an oncogene in squamous cell carcinomas (SCCs). Because ?Np63? and p53 bind virtually identical DNA sequence motifs, it has been proposed that ?Np63? functions as a dominant-negative inhibitor of p53 to promote proliferation and block apoptosis. However, most SCCs concurrently overexpress ?Np63? and inactivate p53, suggesting the autonomous action of these oncogenic events. Here we report the discovery of a novel mechanism of transcriptional repression by ?Np63? that reconciles these observations. We found that although both proteins bind the same genomic sites, they regulate largely nonoverlapping gene sets. Upon activation, p53 binds all enhancers regardless of ?Np63? status but fails to transactivate genes repressed by ?Np63?. We found that ?Np63? associates with the SRCAP chromatin regulatory complex involved in H2A/H2A.Z exchange and mediates H2A.Z deposition at its target loci. Interestingly, knockdown of SRCAP subunits or H2A.Z leads to specific induction of ?Np63?-repressed genes. We identified SAMD9L as a key anti-proliferative gene repressed by ?Np63? and H2A.Z whose depletion suffices to reverse the arrest phenotype caused by ?Np63? knockdown. Collectively, these results illuminate a molecular pathway contributing to the autonomous oncogenic effects of ?Np63?.

SUBMITTER: Gallant-Behm CL 

PROVIDER: S-EPMC3475804 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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ΔNp63α represses anti-proliferative genes via H2A.Z deposition.

Gallant-Behm Corrie L CL   Ramsey Matthew R MR   Bensard Claire L CL   Nojek Ignacio I   Tran Jack J   Liu Minghua M   Ellisen Leif W LW   Espinosa Joaquín M JM  

Genes & development 20120926 20


ΔNp63α is a member of the p53 family of transcription factors that functions as an oncogene in squamous cell carcinomas (SCCs). Because ΔNp63α and p53 bind virtually identical DNA sequence motifs, it has been proposed that ΔNp63α functions as a dominant-negative inhibitor of p53 to promote proliferation and block apoptosis. However, most SCCs concurrently overexpress ΔNp63α and inactivate p53, suggesting the autonomous action of these oncogenic events. Here we report the discovery of a novel mec  ...[more]

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