Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses

Significance Previous studies have demonstrated that p21 occupies a central position in cell-cycle regulation and DNA damage responses. As an unstable protein, the regulation of p21 stability has been extensively investigated over the past 20 years. Although p21 degradation by the ubiquitin-proteasome pathway has been well characterized, it is unclear whether ubiquitylated p21 can be recycled. Here, we identify USP11 as a deubiquitylase that directly removes p21 polyubiquitylation and stabilizes p21 protein, revealing that cellular p21 protein is finely regulated by a dynamic balance of USP11-mediated stabilization and proteasome-mediated degradation. Meanwhile, we also provide evidence that the USP11-p21 axis plays a crucial role in G1/S transition under physiological conditions and in regulating the balance between cytostasis and apoptosis.