Heterochromatin silencing of p53 target genes by a small viral protein

Abstract

The transcription factor p53 guards against tumor and virus replication and is inactivated in almost all cancers. p53 activated transcription of target genes is thought to be synonymous with the stabilization of p53 in response to oncogenes and DNA damage. During adenovirus replication, the degradation of p53 by E1B-55k is considered essential for p53 inactivation, and is the basis for p53 selective viral cancer therapies. Here we reveal a dominant epigenetic mechanism that silences p53-activated transcription, irrespective of p53 phosphorylation and stabilization. We show that another adenoviral protein, E4-ORF3, inactivates p53 independently of E1B-55k by forming a nuclear structure that induces de novo H3K9me3 heterochromatin formation at p53 target promoters, preventing p53 DNA-binding. This suppressive nuclear web is highly selective in silencing p53 promoters and operates in the backdrop of global transcriptional changes that drive oncogenic replication. These findings are important for understanding how high levels of wild-type p53 might also be inactivated in cancer as well as the mechanisms that induce aberrant epigenetic silencing of tumor suppressor loci. Our study changes the longstanding definition of how p53 is inactivated in adenovirus infection and provides key insights that could enable the development of true p53 selective oncolytic viral therapies.

Gene-viro-therapy targeting liver cancer by a dual-regulated oncolytic adenoviral vector harboring IL-24 and TRAIL

“…It has been shown that deleting a small viral protein E4-orf3 can bring higher safety to the oncolytic adenovirus; 22 and liver cancer suppressor gene, such as HCCS1 or SOCS3, Liver cancer-targeting gene-viro-therapy X Liu et al have been shown to specifically inhibit liver tumorigenesis. 19,23 It will be our future interest to improve the presently used HCC-targeting OV Ad Á AFP Á D55 and select more appropriate antitumor genes using these strategies.…”

Molecular dynamics of the full-length p53 monomer

“…p53 is in fact a powerful transcription factor, and, consequently, it drives a large number of promoters, 7 depending on specific activators. [8][9][10][11] Possibly the most studied promoter target is p21, [12][13][14] but new targets emerge as, for example, the connection between IL-7Ra and telomer erosion 15 or the silencing of repeats and noncoding RNA. 16 As a consequence of the transactivation of so many different promoters so far described, p53 is able to activate different biochemical pathways affecting the regulation of life and death of the cell.…”

Biophysical and Functional Analyses Suggest That Adenovirus E4-ORF3 Protein Requires Higher-order Multimerization to Function against Promyelocytic Leukemia Protein Nuclear Bodies

“…Either mechanism alone is sufficient to inhibit a DDR and allow efficient Ad DNA replication to occur. Finally, the E4-ORF3 protein inhibits p53-induced gene expression by establishing heterochromatin at p53-responsive cellular promoter regions (28). The E4-ORF3 and E1B-55K⅐E4-ORF6 proteins are multifunctional and play additional roles in the viral life cycle, including the promotion of cell cycle-independent viral replication, the regulation of viral late mRNA splicing and cytoplasmic mRNA accumulation, and the regulation of late protein translation (29 -37).…”