A redox switch in p21-CDK feedback during G2 phase controls the proliferation-cell cycle exit decision

Area of Science:

• Cell Biology
• Biochemistry
• Proteomics

Background:

• Reactive oxygen species (ROS) are crucial signaling molecules affecting cell proliferation and fate.
• Oxidation of cysteine residues (S-sulfenylation) is a key mechanism, but specific targets and regulation are unclear.

Purpose of the Study:

• Identify cell-cycle-coordinated S-sulfenylation events using redox proteomics.
• Investigate the functional role of S-sulfenylation in controlling cell proliferation.

Main Methods:

• Redox proteomics to identify S-sulfenylation targets.
• Analysis of protein oxidation during cell cycle progression.
• Functional assays to determine the role of S-sulfenylation in p21 regulation.

Main Results:

• Identified dynamic S-sulfenylation on a subset of cysteines, despite constant overall proteome oxidation.
• Discovered a critical redox-sensitive cysteine (C41) in p21, a cyclin-dependent kinase (CDK) inhibitor.
• Demonstrated that C41 oxidation regulates p21 interaction with CDK2/CDK4, controlling p21 stability and cell proliferation post-irradiation.

Conclusions:

• S-sulfenylation of p21 by ROS is a critical regulatory mechanism for cell cycle control.
• Oxidation of p21's C41 residue influences its stability and function, impacting cell fate decisions.
• Suggests a broader coordination between cell cycle progression and redox control through S-sulfenylation of multiple regulators.