SIRT1 modulates cell cycle progression by regulating CHK2 acetylation−phosphorylation

Wenyu Zhang; Yanling Feng; Qiqiang Guo; Wendong Guo; Hongde Xu; Xiaoman Li; Fei Yi; Yi Guan; Nanxi Geng; Pingyuan Wang; Longyue Cao; Brian P. O’Rourke; Juhyeon Jo; Jiyun Kwon; Ruihong Wang; Xiaoyu Song; In Hye Lee; Liu Cao

doi:10.1038/s41418-019-0369-7

SIRT1 modulates cell cycle progression by regulating CHK2 acetylation−phosphorylation

Wenyu Zhang, Yanling Feng, Qiqiang Guo, Wendong Guo, Hongde Xu, Xiaoman Li, Fei Yi, Yi Guan, Nanxi Geng, Pingyuan Wang, Longyue Cao, Brian P. O’Rourke, Juhyeon Jo, Jiyun Kwon, Ruihong Wang, Xiaoyu Song, In Hye Lee, Liu Cao

Life Sciences

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

Both the stress-response protein, SIRT1, and the cell cycle checkpoint kinase, CHK2, play critical roles in aging and cancer via the modulation of cellular homeostasis and the maintenance of genomic integrity. However, the underlying mechanism linking the two pathways remains elusive. Here, we show that SIRT1 functions as a modifier of CHK2 in cell cycle control. Specifically, SIRT1 interacts with CHK2 and deacetylates it at lysine 520 residue, which suppresses CHK2 phosphorylation, dimerization, and thus activation. SIRT1 depletion induces CHK2 hyperactivation-mediated cell cycle arrest and subsequent cell death. In vivo, genetic deletion of Chk2 rescues the neonatal lethality of Sirt1^−/− mice, consistent with the role of SIRT1 in preventing CHK2 hyperactivation. Together, these results suggest that CHK2 mediates the function of SIRT1 in cell cycle progression, and may provide new insights into modulating cellular homeostasis and maintaining genomic integrity in the prevention of aging and cancer.

Original language	English
Pages (from-to)	482-496
Number of pages	15
Journal	Cell Death and Differentiation
Volume	27
Issue number	2
DOIs	https://doi.org/10.1038/s41418-019-0369-7
State	Published - 1 Feb 2020

Bibliographical note

Funding Information:
Acknowledgements This work was supported by National Key R&D Program of China (2016YFC1302400), the Ministry of Education Innovation Team Development Plan (IRT_17R107&IRT13101), the Key Project of the National Natural Science Foundation (81130042, 81770001), the National Science Foundation of China (31300963, 81502400, 81502447, and 81502414), the Liaoning Education Department General Project (LK201627), and funded by the National Research Foundation of Korea (NRF-2014R1A1A3051320, NRF-2014M3A9D8034459, and NRF-2016R1D1A1B04934603).

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© 2019, The Author(s).

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title = "SIRT1 modulates cell cycle progression by regulating CHK2 acetylation−phosphorylation",

abstract = "Both the stress-response protein, SIRT1, and the cell cycle checkpoint kinase, CHK2, play critical roles in aging and cancer via the modulation of cellular homeostasis and the maintenance of genomic integrity. However, the underlying mechanism linking the two pathways remains elusive. Here, we show that SIRT1 functions as a modifier of CHK2 in cell cycle control. Specifically, SIRT1 interacts with CHK2 and deacetylates it at lysine 520 residue, which suppresses CHK2 phosphorylation, dimerization, and thus activation. SIRT1 depletion induces CHK2 hyperactivation-mediated cell cycle arrest and subsequent cell death. In vivo, genetic deletion of Chk2 rescues the neonatal lethality of Sirt1−/− mice, consistent with the role of SIRT1 in preventing CHK2 hyperactivation. Together, these results suggest that CHK2 mediates the function of SIRT1 in cell cycle progression, and may provide new insights into modulating cellular homeostasis and maintaining genomic integrity in the prevention of aging and cancer.",

author = "Wenyu Zhang and Yanling Feng and Qiqiang Guo and Wendong Guo and Hongde Xu and Xiaoman Li and Fei Yi and Yi Guan and Nanxi Geng and Pingyuan Wang and Longyue Cao and O{\textquoteright}Rourke, {Brian P.} and Juhyeon Jo and Jiyun Kwon and Ruihong Wang and Xiaoyu Song and Lee, {In Hye} and Liu Cao",

note = "Funding Information: Acknowledgements This work was supported by National Key R&D Program of China (2016YFC1302400), the Ministry of Education Innovation Team Development Plan (IRT_17R107&IRT13101), the Key Project of the National Natural Science Foundation (81130042, 81770001), the National Science Foundation of China (31300963, 81502400, 81502447, and 81502414), the Liaoning Education Department General Project (LK201627), and funded by the National Research Foundation of Korea (NRF-2014R1A1A3051320, NRF-2014M3A9D8034459, and NRF-2016R1D1A1B04934603). Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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T1 - SIRT1 modulates cell cycle progression by regulating CHK2 acetylation−phosphorylation

AU - Zhang, Wenyu

AU - Feng, Yanling

AU - Guo, Qiqiang

AU - Guo, Wendong

AU - Xu, Hongde

AU - Li, Xiaoman

AU - Yi, Fei

AU - Guan, Yi

AU - Geng, Nanxi

AU - Wang, Pingyuan

AU - Cao, Longyue

AU - O’Rourke, Brian P.

AU - Jo, Juhyeon

AU - Kwon, Jiyun

AU - Wang, Ruihong

AU - Song, Xiaoyu

AU - Lee, In Hye

AU - Cao, Liu

N1 - Funding Information: Acknowledgements This work was supported by National Key R&D Program of China (2016YFC1302400), the Ministry of Education Innovation Team Development Plan (IRT_17R107&IRT13101), the Key Project of the National Natural Science Foundation (81130042, 81770001), the National Science Foundation of China (31300963, 81502400, 81502447, and 81502414), the Liaoning Education Department General Project (LK201627), and funded by the National Research Foundation of Korea (NRF-2014R1A1A3051320, NRF-2014M3A9D8034459, and NRF-2016R1D1A1B04934603). Publisher Copyright: © 2019, The Author(s).

PY - 2020/2/1

Y1 - 2020/2/1

N2 - Both the stress-response protein, SIRT1, and the cell cycle checkpoint kinase, CHK2, play critical roles in aging and cancer via the modulation of cellular homeostasis and the maintenance of genomic integrity. However, the underlying mechanism linking the two pathways remains elusive. Here, we show that SIRT1 functions as a modifier of CHK2 in cell cycle control. Specifically, SIRT1 interacts with CHK2 and deacetylates it at lysine 520 residue, which suppresses CHK2 phosphorylation, dimerization, and thus activation. SIRT1 depletion induces CHK2 hyperactivation-mediated cell cycle arrest and subsequent cell death. In vivo, genetic deletion of Chk2 rescues the neonatal lethality of Sirt1−/− mice, consistent with the role of SIRT1 in preventing CHK2 hyperactivation. Together, these results suggest that CHK2 mediates the function of SIRT1 in cell cycle progression, and may provide new insights into modulating cellular homeostasis and maintaining genomic integrity in the prevention of aging and cancer.

AB - Both the stress-response protein, SIRT1, and the cell cycle checkpoint kinase, CHK2, play critical roles in aging and cancer via the modulation of cellular homeostasis and the maintenance of genomic integrity. However, the underlying mechanism linking the two pathways remains elusive. Here, we show that SIRT1 functions as a modifier of CHK2 in cell cycle control. Specifically, SIRT1 interacts with CHK2 and deacetylates it at lysine 520 residue, which suppresses CHK2 phosphorylation, dimerization, and thus activation. SIRT1 depletion induces CHK2 hyperactivation-mediated cell cycle arrest and subsequent cell death. In vivo, genetic deletion of Chk2 rescues the neonatal lethality of Sirt1−/− mice, consistent with the role of SIRT1 in preventing CHK2 hyperactivation. Together, these results suggest that CHK2 mediates the function of SIRT1 in cell cycle progression, and may provide new insights into modulating cellular homeostasis and maintaining genomic integrity in the prevention of aging and cancer.

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ER -

SIRT1 modulates cell cycle progression by regulating CHK2 acetylation−phosphorylation

Abstract

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