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Deacetylation of CHK2 by SIRT1 protects cells from oxidative stress-dependent DNA damage response.

ABSTRACT: Growing evidence indicates that metabolic signaling pathways are interconnected to DNA damage response (DDR). However, factors that link metabolism to DDR remain incompletely understood. SIRT1, an NAD+-dependent deacetylase that regulates metabolism and aging, has been shown to protect cells from DDR. Here, we demonstrate that SIRT1 protects cells from oxidative stress-dependent DDR by binding and deacetylating checkpoint kinase 2 (CHK2). We first showed that essential proteins in DDR were hyperacetylated in Sirt1-deficient cells and that among them, the level of acetylated CHK2 was highly increased. We found that Sirt1 formed molecular complexes with CHK2, BRCA1/BRCA2-associated helicase 1 (BACH1), tumor suppressor p53-binding protein 1 (53BP1), and H2AX, all of which are key factors in response to DNA damage. We then demonstrated that CHK2 was normally inhibited by SIRT1 via deacetylation but dissociated with SIRT1 under oxidative stress conditions. This led to acetylation and activation of CHK2, which increased cell death under oxidative stress conditions. Our data also indicated that SIRT1 deacetylated the K235 and K249 residues of CHK2, whose acetylation increased cell death in response to oxidative stress. Thus, SIRT1, a metabolic sensor, protects cells from oxidative stress-dependent DDR by the deacetylation of CHK2. Our findings suggest a crucial function of SIRT1 in inhibiting CHK2 as a potential therapeutic target for cancer treatment.

SUBMITTER: Kwon J

PROVIDER: S-EPMC6430805 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Deacetylation of CHK2 by SIRT1 protects cells from oxidative stress-dependent DNA damage response.

Kwon Jiyun J Lee Suhee S Kim Yong-Nyun YN Lee In Hye IH

Experimental & molecular medicine 20190322 3

Growing evidence indicates that metabolic signaling pathways are interconnected to DNA damage response (DDR). However, factors that link metabolism to DDR remain incompletely understood. SIRT1, an NAD<sup>+</sup>-dependent deacetylase that regulates metabolism and aging, has been shown to protect cells from DDR. Here, we demonstrate that SIRT1 protects cells from oxidative stress-dependent DDR by binding and deacetylating checkpoint kinase 2 (CHK2). We first showed that essential proteins in DDR ...[more]

PMID: 30902968

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Project description:Autophagy is a catabolic pathway activated in response to different cellular stressors, such as damaged organelles, accumulation of misfolded or unfolded proteins, ER stress, accumulation of reactive oxygen species, and DNA damage. Some DNA damage sensors like FOXO3a, ATM, ATR, and p53 are known to be important autophagy regulators, and autophagy seems therefore to have a role in DNA damage response (DDR). Recent studies have partly clarified the pathways that induce autophagy during DDR, but its precise role is still not well known. Previous studies have shown that autophagy alterations induce an increase in DNA damage and in the occurrence of tumor and neurodegenerative diseases, highlighting its fundamental role in the maintenance of genomic stability. During DDR, autophagy could act as a source of energy to maintain cell cycle arrest and to sustain DNA repair activities. In addition, autophagy seems to play a role in the degradation of components involved in the repair machinery. In this paper, molecules which are able to induce oxidative stress and/or DNA damage have been selected and their toxic and genotoxic effects on the U937 cell line have been assessed in the presence of the single compounds and in concurrence with an inhibitor (chloroquine) or an inducer (rapamycin) of autophagy. Our data seem to corroborate the fundamental role of this pathway in response to direct and indirect DNA-damaging agents. The inhibition of autophagy through chloroquine had no effect on the genotoxicity induced by the tested compounds, but it led to a high increase of cytotoxicity. The induction of autophagy, through cotreatment with rapamycin, reduced the genotoxic activity of the compounds. The present study confirms the cytoprotective role of autophagy during DDR; its inhibition can sensitize cancer cells to DNA-damaging agents. The modulation of this pathway could therefore be an innovative approach able to reduce the toxicity of many compounds and to enhance the activity of others, including anticancer drugs.

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Deacetylation of CHK2 by SIRT1 protects cells from oxidative stress-dependent DNA damage response.

Publications

Deacetylation of CHK2 by SIRT1 protects cells from oxidative stress-dependent DNA damage response.

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