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The histone acetyltransferase PCAF regulates p21 transcription through stress-induced acetylation of histone H3. | LitMetric

AI Article Synopsis

  • The p53 tumor suppressor functions mainly by activating target genes to combat DNA damage or other stresses, with the help of various histone acetyl transferases (HATs) like PCAF, which is essential for p53-dependent expression of the cdk inhibitor p21.
  • PCAF's involvement is crucial for activating p21 in response to different stressors, and cells without PCAF cannot halt cell division when exposed to specific p53 activators like nutlin-3 or p14(ARF), indicating its significant role in the p53 signaling pathway.
  • Interestingly, PCAF influences p21 expression independently of its effect on p53 acetylation; instead, it is essential

Article Abstract

The activity of p53 as a tumor suppressor primarily depends on its ability to transactivate specific target genes in response to genotoxic and other potentially mutagenic stresses. Several histone acetyl transferases (HATs), including p300, CBP, PCAF and GCN5 have been implicated in the activation of p53-dependent transcription of the cyclin-dependent kinase (cdk) inhibitor p21 as well as other target genes. Here we show that PCAF, but not CBP or p300, is a critical regulator of p53-dependent p21 expression in response to multiple p53-activating stresses. PCAF was required for the transcriptional activation of p21 in response to exogenous p53 in p53-null cells, nutlin-3, DNA damaging agents and p14(ARF) expression, suggesting a broad requirement for PCAF in p53 signaling to p21 after stress. Importantly, cells lacking PCAF failed to undergo cell cycle arrest in response to nutlin-3 treatment or p14(ARF) expression, consistent with a physiologically important role for PCAF in this p53 function. Surprisingly, the role for PCAF in induction of p21 was independent of p53 lysine 320 acetylation, a previously suggested target of PCAF-mediated acetylation. Though p21 promoter occupancy by p53 was not altered by PCAF knockdown, activation of p21 transcription required an intact PCAF HAT domain, and induction of chromatin marks acetyl-H3K9 and acetyl-H3K14 at the p21 promoter by p53 was dependent upon physiologic levels of PCAF. Together, our experiments indicate that PCAF is required for stress-responsive histone 3 acetylation at the p21 promoter, p53-directed transcription of p21 and the resultant growth arrest.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404877PMC
http://dx.doi.org/10.4161/cc.20864DOI Listing

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