Experimental Insights into the Interplay between Histone Modifiers and p53 in Regulating Gene Expression

Abstract

Chromatin structure plays a fundamental role in regulating gene expression, with histone modifiers shaping the structure of chromatin by adding or removing chemical changes to histone proteins. The p53 transcription factor controls gene expression, binds target genes, and regulates their activity. While p53 has been extensively studied in cancer research, specifically in relation to fundamental cellular processes, including gene transcription, apoptosis, and cell cycle progression, its association with histone modifiers has received limited attention. This review explores the interplay between histone modifiers and p53 in regulating gene expression. We discuss how histone modifications can influence how p53 binds to target genes and how this interplay can be disrupted in cancer cells. This review provides insights into the complex mechanisms underlying gene regulation and their implications for potential cancer therapy.

Keywords: cancer; chromatin structure; gene regulation; histone modifications; p53.

Figure 1

Histone modifications. (A) Methylation and demethylation are catalyzed by histone methyltransferase and histone demethylase, respectively. Euchromatin is characterized by specific molecular marks that indicate active gene expression, including histone acetylation, H3K4 trimethylation (H3K4me3), and H3K36 trimethylation (H3K36me3). In contrast, heterochromatin is marked by different modifications associated with gene repression and chromatin compaction. These marks include H3K9 trimethylation (H3K9me3) and H3K27 trimethylation (H3K27me3). Acetylation occurs in lysine residues catalyzed by histone acetyltransferase, while deacetylation is catalyzed by histone acetyltransferase. Phosphorylation: Kinases and phosphatases are enzymes involved in the addition and removal of phosphate groups, respectively, on proteins [24]. (B) Protein methylation occurs on lysine and arginine residues in histone and non-histone proteins through protein methyltransferases. The specific methyltransferases and demethylases reversibly regulated lysine methylation and demethylation from mono to trimethylation. Arginine methylations are induced in three types, including monomethylation, asymmetric dimethylation, and symmetric dimethylation [25]. (C) Acetyltransferases (KATs) transfer the acetyl group from acetyl–CoA to specific lysine residues in proteins, while acetylation can be reversed by lysine deacetylases (KDACs). (D) Protein phosphorylation occurs in serine, threonine, and tyrosine residues [26]. (E) Histone modifiers and p53 interact through mechanisms: Indirect chromatin modifications and direct recruitment target genes, affecting gene expression.

Figure 2

SET7/9 methylation activates p53, which leads to the transcriptional activation of p21 gene expression, as well as p53-mediated apoptosis and cell cycle arrest.

Figure 3

G9a has the potential to modulate p53 transcriptional activity in a differential manner. (A) In humans, G9a functions as a coactivator for p53 by recruiting histone acetyltransferases (HATs) such as CBP and PCAF. (B) However, mouse G9a exerts a repressive effect on p53 transcriptional activity.

Figure 4

PRMT5 methylates H4R3, indirectly influencing p53 activity by affecting the transcriptional regulation of p53 target genes. (A) Arginine methylation-induced bypassing of p53 leads to the evasion of apoptosis and facilitates tumor growth, whereas the depletion of PRMT5 induces p53-mediated apoptosis. (B) PRMT5 controls the alternative splicing of key histone-modifying enzymes such as TIP60 and KMT5C, thereby influencing chromatin structure and influencing DNA repair pathway.

Figure 5

In response to DNA damage, p53 binds to a p53-consensus motif in the JMJD2B promoter; hence, p53 controls the expression of the JMJD2B gene. The induction of JMJD2B, in turn, suppresses the transcription of important p53 targets, such as p21, PIG3, and PUMA.

Figure 6

The competition between Ezh2 and p53 regulates inflammasome activation in mice. Upon exposure to inflammasome inducers, Ezh2 inhibits the binding of p53 to the promoter region of the lncRNA Neat1 gene. As a result, the recruitment of SIRT1 by p53 is also disrupted, preventing its binding to the DNA. This process leads to the enrichment of H3K27ac. Subsequently, the facilitated transcription of Neat1 by p65 promotes the activation of the inflammasome.

Figure 7

Phosphorylation of p53 at multiple sites in response to DNA damage regulates its transcriptional activity, DNA binding affinity, and protection against degradation. Phosphorylation at Ser15 and Ser20 enhances transcriptional activity and prevents ubiquitin-mediated degradation, respectively. Phosphorylation at Ser-392 enhances sequence-specific DNA binding and stabilizes tetramer formation following UV irradiation.

Figure 8

(A) p38 phosphorylates p53, at Ser15 and Ser392, activating p53 and increasing its stability, transcriptional activity, and induction of target genes involved in cell cycle arrest, DNA repair, and apoptosis. Ser15 phosphorylation also stabilizes p53 by reducing its interaction with MDM2. (B) Upon activation by p38, 1/2 phosphorylates histone H3 at Ser10 and Ser28, modulating chromatin structure and gene expression. (C) When activated by the p38 MAPK pathway, MSK1 interacts with p53 and is recruited to the p21 promoter, where it phosphorylates histone H3 in a p53-dependent manner.

Figure 9

Upon stimulation with UV or EGF, activated RSK2 phosphorylates p53 at Ser15, and the RSK2/p53 complex translocates to the nucleus, where RSK2 phosphorylates histone H3 at Ser10, contributing to transcriptional regulation, chromatin remodeling, and cell cycle control.

Figure 10

Following DNA damage caused by irradiation, lysine residues of p53 undergo acetylation. This acetylation leads to the recruitment of coactivators such as CBP/p300 and TRRAP to the p21 promoter, thereby increasing histone acetylation. Meanwhile, SIRT1-mediated K382 deacetylation inhibits p53’s transcriptional activation, promoting its degradation.

Figure 11

Upon DNA damage, Tip60 interacts with p53 and binds to its target gene promoters, leading to p21 activation and growth arrest. Additionally, Tip60 induces K120 acetylation, resulting in the activation of PUMA expression.