Discovery of p21 redox switch reveals new mechanism controlling cell division and senescence in cancer research

Discovery of p21 redox switch reveals new mechanism controlling cell division and senescence in cancer research

(IN BRIEF) Scientists at the Institute of Cancer Research, London, together with colleagues from TUD Dresden University of Technology, have discovered that oxidation of a single site in the protein p21 acts as a chemical switch determining whether cells keep dividing or permanently stop. Using redox proteomics, the team mapped over 1,700 oxidation sites and identified cysteine 41 of p21 as crucial in directing cell fate. When oxidised, p21 breaks down and allows cells to proliferate, but when left unoxidised, p21 stabilises and promotes senescence, a protective state against cancer that can also contribute to ageing and treatment resistance. Their experiments showed that both genetic mutation and redox regulation could steer this process, confirming its role as a key determinant of cell behaviour. The findings, published in Molecular Cell, highlight redox signalling as a central regulatory mechanism and suggest new therapeutic opportunities for targeting resistant cancers by manipulating p21’s oxidation state.

(PRESS RELEASE) LONDON, 28-Aug-2025 — /EuropaWire/ — Researchers from the Institute of Cancer Research, London, working with colleagues who initiated the project at the Biotechnology Center (BIOTEC) of TUD Dresden University of Technology, have uncovered a molecular switch that helps determine whether cells continue dividing or enter permanent arrest. The discovery sheds light on a fundamental mechanism of cell biology with implications for both cancer treatment and the ageing process.

Image: Artwork illustrating the cell cycle (the fiery ring) and the role of the protein p21 (white structure). A tiny chemical switch on p21 helps decide whether cells continue to divide – or enter senescence, a ‘frozen’ state where they stop for good (represented by the ice below). Artwork designed and provided by postdoc Hinyuk Lai.

The team’s work, published in Molecular Cell, reveals that the fate of a cell is influenced by a subtle chemical modification to p21, a protein long known for its role in halting uncontrolled cell division. The modification occurs through oxidation – a process driven by reactive oxygen species (ROS), which are natural byproducts of cellular metabolism. This oxidation event acts on a single amino acid, cysteine 41, and changes how p21 functions and interacts with other proteins.

When this site is oxidised just before a cell divides, p21 is broken down, enabling cell growth and reproduction. In contrast, when the site is not oxidised, p21 becomes more stable, pushing cells toward senescence – a permanent stop in division that helps guard against cancer but can also contribute to ageing and treatment resistance if dysregulated.

To map the process, the researchers applied redox proteomics, a technique that tracks protein modifications caused by ROS across the cell cycle. By analysing more than 1,700 oxidation sites, they produced one of the most detailed views to date of how redox signalling operates during cell division. Their focus on p21 revealed that cells engineered with a non-oxidisable mutation at cysteine 41 accumulated more stable p21 proteins, entered senescence more often after stress such as radiotherapy, and were ultimately outcompeted by normal cells.

Importantly, the team confirmed that this effect was not limited to genetic mutation. By using targeted antioxidant enzymes to maintain p21 in a reduced state, they saw the same increase in senescence, demonstrating that redox regulation alone could drive these changes.

Senior author Dr Jörg Mansfeld, Group Leader of the Post-translational Modifications and Cell Proliferation Group in the Division of Cell and Molecular Biology at the ICR, explained: “It’s remarkable that such a small chemical change – just one oxidised cysteine – can have such a profound impact on how cells behave. It shows how finely tuned our cell cycle controls really are.”

The findings suggest that manipulating the redox state of p21 could become a therapeutic strategy, particularly for cancers where p21 is present but misregulated or where resistance to standard treatments develops. By altering this redox control, researchers hope to boost the effectiveness of therapies like radiotherapy or targeted drugs that elevate p21 levels.

Co-lead author Dr Julia Vorhauser, Postdoctoral Training Fellow at the ICR, added: “By understanding how p21’s oxidation state controls its stability and interactions, we’ve uncovered a completely new layer of regulation in the cell cycle. This could be a useful target in cancer – especially in tumours where p21 is present but misregulated.”

The work also builds on earlier studies from the same team showing that CDK2, another cell cycle regulator inhibited by p21, is directly influenced by oxidation. Together, these discoveries underline that redox control is not merely a byproduct of cell stress but a central system for regulating growth, repair, and ageing. The researchers are now investigating how this chemical switch functions in different cancer types and whether it can be harnessed to design more effective combination treatments.

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SOURCE: The Institute of Cancer Research