SIRT1 modulates cell cycle progression by regulating CHK2 acetylation\u2212phosphorylation

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

doi:10.1038/s41418-019-0369-7

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.

Highlights

DNA damage influences SIRT1 activity and SIRT1-dependent deacetylation regulates cell cycle checkpoint proteins, it remains unknown whether CHK2 is regulated by SIRT1 [24,25,26]
We reveal that acetylation/deacetylation modulates the function of CHK2 in cell cycle by
Previous studies have demonstrated that SIRT1 mutant cells displayed p53 hyperacetylation upon DNA damage and increased ionizing radiation (IR)-induced apoptosis in thymocytes [21]

Summary

Introduction

Previous studies have suggested that CHK2 is a key component in several molecular processes involved in DNA structural modification, cell cycle. Among the sirtuin family of protein deacetylases (SIRT1–7), whose catalytic activity is uniquely dependent on NAD+, SIRT1 shares the highest mammalian homology with the yeast silent information regulator 2 [11, 12]. As the most well-studied sirtuin, SIRT1 has been implicated in many physiological and pathophysiological processes, including the circadian clock, neuronal protection, caloric restriction, cell cycle arrest, apoptosis, glucose and lipid metabolism, cellular senescence, and cancer [13,14,15,16,17,18,19]. Our study reveals that a SIRT1-regulated acetylation pathway mediates CHK2 activation and suggests that the SIRT1–CHK2 axis is required for genomic integrity and cellular homeostasis

Results

Discussion

Materials and methods

Compliance with ethical standards