p53 protein rewrites cancer rules: Signalling guides immune response

Researchers at The Wistar Institute have overturned decades of accepted wisdom about p53 – the so-called ‘guardian of the genome’ – revealing that this crucial tumour suppressor is far more sophisticated than previously believed.

For 30 years, scientists assumed that p53 activated the same set of genes regardless of the situation, leaving the cell itself to decide whether to halt division or self-destruct. But a study published in Molecular Cell [1] shows that p53 can, in fact, interpret cellular signals and direct distinct genetic programmes, including those that enlist the immune system to destroy cancer cells.

The team discovered that p53’s behaviour is shaped by an enzyme called PADI4, which modifies p53 through a chemical process known as citrullination. This subtle alteration changes where p53 binds on DNA - prompting it to abandon many of its usual target genes and relocate to regions associated with immune response activation.

“p53 isn’t as simple as we once thought,” said Maureen Murphy, PhD, Deputy Director of Wistar’s Ellen and Ronald Caplan Cancer Center and senior author of the study. “It can ‘read’ intracellular signals and decide where to act, and that decision appears to mobilise the immune system against tumours.”

Murphy’s group has long studied genetic variants of p53 found in families of African descent, some of which are only partially functional. Comparing these hypomorphic variants to normal p53 led the researchers to identify PADI4 as a key missing link. When PADI4 is active, it rewires p53’s binding profile, enhancing immune-related gene expression.

Using advanced techniques including ChIP-seq and CUT&Tag, the team mapped these changes in live cells and confirmed the effect in mouse models. They found that when p53 is citrullinated, around 30% of its conventional binding sites are replaced by new ones that drive interferon signalling – the cell’s core antiviral and anti-tumour response.

The findings carry important clinical implications. Patients with certain p53 variants that fail to activate PADI4 may respond poorly to immunotherapies, suggesting that PADI4 status could serve as a biomarker for personalised treatment decisions.

“By understanding how p53 collaborates with PADI4, we may be able to predict who will benefit most from immune-based cancer therapies,” said Murphy.

Beyond its therapeutic potential, the work highlights the value of studying genetic diversity in underrepresented populations. “By examining p53 variants in families of African ancestry – people often left out of research – we uncovered a fundamental new mechanism of tumour suppression,” Murphy added.

More information online

1.    Targeted Citrullination Enables p53 Binding to Non-canonical Sites published in Molecular Cell, 2025. Online publication.