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

Tanggang Deng; Guobei Yan; Xin Song; Lin Xie; Yu Zhou; Jianglin Li; Xiaoxiao Hu; Zhen Li; Jun Hu; Yibin Zhang; Hui Zhang; Yang Sun; Peifu Feng; Dong Wei; Bin Hu; Jing Liu; Weihong Tan; Mao Ye

doi:10.1073/pnas.1714938115

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

Proc Natl Acad Sci U S A. 2018 May 1;115(18):4678-4683. doi: 10.1073/pnas.1714938115. Epub 2018 Apr 16.

Authors

Tanggang Deng^{1

2}, Guobei Yan^{1

2}, Xin Song³, Lin Xie^{1

2}, Yu Zhou^{1

2}, Jianglin Li^{1

2}, Xiaoxiao Hu^{1

2}, Zhen Li³, Jun Hu^{1

2}, Yibin Zhang⁴, Hui Zhang^{1

2}, Yang Sun^{1

2}, Peifu Feng^{1

2}, Dong Wei^{1

2}, Bin Hu^{1

2}, Jing Liu⁵, Weihong Tan^{6

2}, Mao Ye^{6

2}

Affiliations

¹ Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, 410082 Hunan, China.
² Aptamer Engineering Center of Hunan Province, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 Hunan, China.
³ Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118 Yunnan, China.
⁴ Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078 Hunan, China.
⁵ Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078 Hunan, China [email protected] [email protected] [email protected].
⁶ Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, 410082 Hunan, China; [email protected] [email protected] [email protected].

Abstract

p21^WAF1/CIP1 is a broad-acting cyclin-dependent kinase inhibitor. Its stability is essential for proper cell-cycle progression and cell fate decision. Ubiquitylation by the multiple E3 ubiquitin ligase complexes is the major regulatory mechanism of p21, which induces p21 degradation. However, it is unclear whether ubiquitylated p21 can be recycled. In this study, we report USP11 as a deubiquitylase of p21. In the nucleus, USP11 binds to p21, catalyzes the removal of polyubiquitin chains conjugated onto p21, and stabilizes p21 protein. As a result, USP11 reverses p21 polyubiquitylation and degradation mediated by SCF^SKP2, CRL4^CDT2, and APC/C^CDC20 in a cell-cycle-independent manner. Loss of USP11 causes the destabilization of p21 and induces the G1/S transition in unperturbed cells. Furthermore, p21 accumulation mediated by DNA damage is completely abolished in cells depleted of USP11, which results in abrogation of the G2 checkpoint and induction of apoptosis. Functionally, USP11-mediated stabilization of p21 inhibits cell proliferation and tumorigenesis in vivo. These findings reveal an important mechanism by which p21 can be stabilized by direct deubiquitylation, and they pinpoint a crucial role of the USP11-p21 axis in regulating cell-cycle progression and DNA damage responses.

Keywords: USP11; cell cycle; deubiquitylation; p21; ubiquitin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Apoptosis / genetics
Cell Cycle*
Cell Nucleus / genetics
Cell Nucleus / metabolism*
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
DNA Damage*
HEK293 Cells
Humans
Proteolysis
Signal Transduction*
Ubiquitin-Specific Proteases / genetics
Ubiquitin-Specific Proteases / metabolism*
Ubiquitination / genetics

Substances

CDKN1A protein, human
Cyclin-Dependent Kinase Inhibitor p21
USP1 protein, human
Ubiquitin-Specific Proteases

Grants and funding

T32 HG000044/HG/NHGRI NIH HHS/United States