Post-translational histone modifications play important roles in chromatin functions, ranging from DNA damage and repair, DNA recombination, chromatin structure, to gene regulation. p53 is a tumor suppressor and transcription factor that recruits both coactivators (e.g., histone acetyltransferases and protein Arg methyltransferases) and corepressors (e.g., histone deacetylases) to its target gene promoters to regulate chromatin structure and gene expression. In addition, the activity of p53 as a tumor suppressor and transcriptional factor is also regulated by numerous post-translational modifications of p53 itself, including phosphorylation, acetylation, and ubiquitination. Histone deacetylases (HDACs) counteract the activity of histone acetyltransferases (HATs) to dynamically regulate histone acetylation and finely adjust the expression of p53 target genes. Although protein Arg methyltransferases (PRMTs) have been found to methylate histone Arg residues to activate p53 target genes, the process to reverse histone Arg methylation is unclear. I have reported that peptidylarginine deiminase 4 (PAD4) can reverse histone Arg methylation via a reaction called demethylimination thereby repressing the estrogen receptor target genes. Recent studies from my group have showed that PAD4 works as a p53 corepressor to counteract the activities of PRMTs and to reverse histone Arg methylation at the p53 target gene p21 promoter. In addition, our preliminary studies demonstrated protein-protein interactions of p53/PAD4/HDAC2. The central hypothesis to be tested in this proposal is that citrullination and deacetylation of histones and p53 regulate p21 expression by overlapping molecular mechanisms. To test this hypothesis, we will 1) characterize nucleosome positioning/density of the p21 promoter and relate the change of chromatin structure with the activation of p21 (Aim 1);2) investigate how PAD4 and HDAC2 cooperate to efficiently repress the expression of p21;3) analyze whether reversible p53 acetylation catalyzed by HAT/HDAC forms a molecular switch to control the p53/PAD4 interaction;4) investigate the effects of p53 citrullination on the p53 activity in DNA binding and gene regulation.
p53 is mutated in about half of human cancers and plays a pivotal role in the cellular response to cope with various stresses, including DNA damage and hypoxia. The role of PAD4 as a p53 corepressor implicates that one can increase the expression of the p53 target genes by blocking the activity of PAD4. Consistent with this idea, inhibition of PAD4 by its inhibitor or depletion of PAD4 by its siRNAs increased the expression of the p53 target gene p21, suggesting that PAD4 is a hopeful novel target for cancer treatment.
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