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

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 i...

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Autores principales: Deng, Tanggang, Yan, Guobei, Song, Xin, Xie, Lin, Zhou, Yu, Li, Jianglin, Hu, Xiaoxiao, Li, Zhen, Hu, Jun, Zhang, Yibin, Zhang, Hui, Sun, Yang, Feng, Peifu, Wei, Dong, Hu, Bin, Liu, Jing, Tan, Weihong, Ye, Mao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939064/
https://www.ncbi.nlm.nih.gov/pubmed/29666278
http://dx.doi.org/10.1073/pnas.1714938115
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author Deng, Tanggang
Yan, Guobei
Song, Xin
Xie, Lin
Zhou, Yu
Li, Jianglin
Hu, Xiaoxiao
Li, Zhen
Hu, Jun
Zhang, Yibin
Zhang, Hui
Sun, Yang
Feng, Peifu
Wei, Dong
Hu, Bin
Liu, Jing
Tan, Weihong
Ye, Mao
author_facet Deng, Tanggang
Yan, Guobei
Song, Xin
Xie, Lin
Zhou, Yu
Li, Jianglin
Hu, Xiaoxiao
Li, Zhen
Hu, Jun
Zhang, Yibin
Zhang, Hui
Sun, Yang
Feng, Peifu
Wei, Dong
Hu, Bin
Liu, Jing
Tan, Weihong
Ye, Mao
author_sort Deng, Tanggang
collection PubMed
description 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.
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spelling pubmed-59390642018-05-09 Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses Deng, Tanggang Yan, Guobei Song, Xin Xie, Lin Zhou, Yu Li, Jianglin Hu, Xiaoxiao Li, Zhen Hu, Jun Zhang, Yibin Zhang, Hui Sun, Yang Feng, Peifu Wei, Dong Hu, Bin Liu, Jing Tan, Weihong Ye, Mao Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2018-05-01 2018-04-16 /pmc/articles/PMC5939064/ /pubmed/29666278 http://dx.doi.org/10.1073/pnas.1714938115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Deng, Tanggang
Yan, Guobei
Song, Xin
Xie, Lin
Zhou, Yu
Li, Jianglin
Hu, Xiaoxiao
Li, Zhen
Hu, Jun
Zhang, Yibin
Zhang, Hui
Sun, Yang
Feng, Peifu
Wei, Dong
Hu, Bin
Liu, Jing
Tan, Weihong
Ye, Mao
Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses
title Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses
title_full Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses
title_fullStr Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses
title_full_unstemmed Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses
title_short Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses
title_sort deubiquitylation and stabilization of p21 by usp11 is critical for cell-cycle progression and dna damage responses
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939064/
https://www.ncbi.nlm.nih.gov/pubmed/29666278
http://dx.doi.org/10.1073/pnas.1714938115
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