Amazing stuff! Cancer is history (soon)!
"... researchers have overturned three decades of scientific thinking about p53, the most important tumor suppressor protein in cancer research. In a study ... they reveal for the first time that this critical protein, responsible for halting cell division or initiating cell death, changes its binding sites according to specific cellular signals. The findings challenge the long-held scientific belief that p53 always activated the same set of genes regardless of cellular context or outcome. Instead, researchers discovered that p53 can be directed by the enzyme PADI4 to leave some of its usual binding sites and relocate to genes that generate an immune response to attack tumors. ...
They also found that PADI4 doesn’t just respond to commands from p53—it actually directs p53’s behavior through a process called citrullination. When PADI4 citrullinates p53 (adding chemical tags to specific amino acid residues), it fundamentally changes where p53 goes in the cell’s DNA. Instead of binding to its usual genes, the modified p53 relocates to genes associated with ETS transcription factors, which are known to regulate immune response genes. ...
This discovery has important implications for cancer treatment and diagnosis. Since certain hypomorphic p53 variants cannot properly activate PADI4, these patients may not respond as well to immunotherapies that rely on the body’s natural immune response to fight cancer. ..."
From the highlights and abstract:
"Highlights
• p53 can be citrullinated in vivo at the C terminus by the protein PADI4
• Endogenous citrullinated p53 can be detected using modification-specific antisera
• Citrullination of p53 redirects it to DNA-binding sites for ETS transcription factors
• Citrullination alters p53 transcriptional potential and tumor suppressor function
Summary
TP53 encodes for the transcription factor p53, which binds to a diverse set of target genes in response to stress.
Activation of p53 results in highly specific transcriptional responses, but the regulation of promoter selectivity by p53 is poorly understood.
Here, we report that sequence-specific binding of p53 is regulated by its target gene and binding partner peptidyl-arginine deiminase 4 (PADI4).
PADI4 enzymatically converts peptidyl-arginine to peptidyl citrulline in a process known as citrullination.
We show that PADI4 citrullinates p53 at the C terminus in vitro, and we confirm two citrullination events in cells and mouse tissue (R306 and R363).
Chromatin immunoprecipitation sequencing (ChIP-seq) reveals that PADI4 expression causes a redirection of p53 away from a subset of canonical binding sites to target genes associated with ETS transcription factors.
Chromatin profiling using citrullination-specific p53 antibodies supports this conclusion. These findings link citrullination to p53 function and illustrate how chromatin modifiers like PADI4 can direct the p53 transcriptional response."
Graphical abstract
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