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.
Highlights
Metabolism and the DNA damage response (DDR)mechanism are essential biological processes for the survival of animals and cells but are generally considered to be two distinct processes
We found that the acetylation levels of BRCA2-associated helicase 1 (BACH1), H2AX, and 53BP1 all modestly increased in SIRT1 knockout mouse cells (Fig. 1a–c)
We showed that SIRT1 protected cells from oxidative stress-dependent DDR by binding to and deacetylating checkpoint kinase 2 (CHK2)
Summary
Metabolism and the DNA damage response (DDR)mechanism are essential biological processes for the survival of animals and cells but are generally considered to be two distinct processes. Metabolism and the DNA damage response (DDR). Ataxia telangiectasia mutated (ATM) and p53, essential factors for DDR, are known crucial regulators of normal metabolism. P53 loss of function mutations can cause metabolic dysfunction, including glucose intolerance and insulin resistance[3,4,5]. Recent studies have indicated that sirtuins regulate DDR and redox signaling[12]. Sirtuins protect cells from ROS-induced damage and regulate the expression of key factors, including nuclear factor E2-related factor 2 (NRF2), in response to oxidative stress[13,14]. When cells are under stress conditions, ROS production is increased, and the sirtuin co-factor NAD+ activates various sirtuins. Sirtuins regulate the activity of antioxidant response element (ARE), which regulates the transcription of pro- and antioxidant
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