Heterochromatin silencing at p53 target genes by a

small viral protein.

p53Revealed character as a tumor

suppressor gene in 1989. Tumor suppressor protein.Encoded by the TP53 gene.Preventing tumor development.Inhibit overexpression of cell.Regulate to cell cycle.

p53 pathway

E1B-55K

55kDa protein.Encoded by E1B genomic region of adenovirus.Binds to p53 and functionally

inactivates it.Inhibit cell death by apoptosis.

ONYX-015

Oncolytic adenoviral therapyDeleted E1B-55KTrialed as a possible treatment for cancer.Be directly injected into a tumor.Combined with chemotherapy

Result

▶Fig 1. p53 is induced and phosphorylated in ΔE1B-55k infection but p53 activity is dominantly suppressed.

Result

▶Fig 1. p53 is induced and phosphorylated in ΔE1B-55k infection but p53 activity is dominantly suppressed.

Result

▶Fig 2. E4-ORF3 inactivates p53 independently of E1B-55k and p53 degradation.

Result

▶Fig 2. E4-ORF3 inactivates p53 independently of E1B-55kand p53 degradation.

Result

▶Fig 3. E4-ORF3 induces heterochromatin formation and prevents p53-DNA binding at endogenous promoters.

Result

▶Fig 3. E4-ORF3 induces heterochromatin formation and prevents p53-DNA binding at endogenous promoters.

Result

▶Fig 3. E4-ORF3 induces heterochromatin formation and prevents p53-DNA binding at endogenous promoters.

Result

▶Fig 4. E4-ORF3 forms a nuclear scaffold that specifies heterochromatin assembly and H3K9 trimethylation at p53 target promoters.

Result

▶Fig 4. E4-ORF3 forms a nuclear scaffold that specifies heterochromatin assembly and H3K9 trimethylation at p53 target promoters.

Result

▶Fig 5. p53 transcriptional targets are silenced selectively in the backdrop of global transcriptional changes that drive oncogenic cellular and viral replication.

Result

▶Fig 5. p53 transcriptional targets are silenced selectively in the backdrop of global transcriptional changes that drive oncogenic cellular and viral replication.

Discussion

• p53 induction and phosphorylation is tantamount to p53 activity, which is the premise for several cancer therapies.

• Identified, E4-ORF3, directing SUV39H1/2 H3K9me3 heterochromatin assembly at p53 target promoters to silence p53 activated transcription in response to genotoxic and oncogenic stress.

Discussion• All of the known targets of E4-ORF3, PML, the MRN

DNA damage/repair complex and Tif1α are subverted by tumor mutations.

• Identification of E4-ORF3 changes the fundamental definition of how p53 is inactivated in adenovirus infected cells, which is a critical mechanistic insight that could now enable the rational development of true p53 tumor selective adenoviral therapies.