A redox switch in p21-CDK feedback during G2 phase controls the proliferation-cell cycle exit decision.
Loading...
Embargo End Date
ICR Authors
Authors
Vorhauser, J
Roumeliotis, TI
Coupe, D
Leung, JK
Yu, L
Böhlig, K
Zerjatke, T
Glauche, I
Nadler, A
Choudhary, JS
Mansfeld, J
Roumeliotis, TI
Coupe, D
Leung, JK
Yu, L
Böhlig, K
Zerjatke, T
Glauche, I
Nadler, A
Choudhary, JS
Mansfeld, J
Document Type
Journal Article
Date
2025-09-04
Date Accepted
2025-07-31
Abstract
Reactive oxygen species (ROS) influence cell proliferation and fate decisions by oxidizing cysteine residues (S-sulfenylation) of proteins, but specific targets and underlying regulatory mechanisms remain poorly defined. Here, we employ redox proteomics to identify cell-cycle-coordinated S-sulfenylation events and investigate their functional role in proliferation control. Although ROS levels rise during cell cycle progression, the overall oxidation of the proteome remains constant, with dynamic S-sulfenylation restricted to a subset of cysteines. Among these, we identify a critical redox-sensitive cysteine residue (C41) in the cyclin-dependent kinase (CDK) inhibitor p21. C41 oxidation regulates the interaction of p21 with CDK2 and CDK4, controlling a double-negative feedback loop that determines p21 stability. When C41 remains reduced, p21's half-life increases in the G2 phase, resulting in more p21 inheritance to daughter cells, suppressing proliferation and promoting senescence after irradiation. Notably, we identify dynamic S-sulfenylation on further cell cycle regulators, implying coordination of cell cycle and redox control.
Citation
Molecular Cell, 2025, 85 (17), pp. 3241 - 3255.e11
Source Title
Molecular Cell
Publisher
CELL PRESS
ISSN
1097-2765
eISSN
1097-4164
Collections
Research Team
Post-transl modification