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Repression of p53 function by SIRT5-mediated desuccinylation at Lysine 120 in response to DNA damage.

ABSTRACT: p53 is a classic tumor suppressor that functions in maintaining genome stability by inducing either cell arrest for damage repair or cell apoptosis to eliminate damaged cells in response to different types of stress. Posttranslational modifications (PTMs) of p53 are thought to be the most effective way for modulating of p53 activation. Here, we show that SIRT5 interacts with p53 and suppresses its transcriptional activity. Using mass spectrometric analysis, we identify a previously unknown PTM of p53, namely, succinylation of p53 at Lysine 120 (K120). SIRT5 mediates desuccinylation of p53 at K120, resulting in the suppression of p53 activation. Moreover, using double knockout mice (p53^-/-Sirt5^-/-), we validate that the suppression of p53 target gene expression and cell apoptosis upon DNA damage is dependent on cellular p53. Our study identifies a novel PTM of p53 that regulates its activation as well as reveals a new target of SIRT5 acting as a desuccinylase.

SUBMITTER: Liu X

PROVIDER: S-EPMC8989948 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Repression of p53 function by SIRT5-mediated desuccinylation at Lysine 120 in response to DNA damage.

Liu Xing X Rong Fangjing F Tang Jinhua J Zhu Chunchun C Chen Xiaoyun X Jia Shuke S Wang Zixuan Z Sun Xueyi X Deng Hongyan H Zha Huangyuan H Ouyang Gang G Xiao Wuhan W

Cell death and differentiation 20211012 4

p53 is a classic tumor suppressor that functions in maintaining genome stability by inducing either cell arrest for damage repair or cell apoptosis to eliminate damaged cells in response to different types of stress. Posttranslational modifications (PTMs) of p53 are thought to be the most effective way for modulating of p53 activation. Here, we show that SIRT5 interacts with p53 and suppresses its transcriptional activity. Using mass spectrometric analysis, we identify a previously unknown PTM o ...[more]

PMID: 34642466

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Project description:The management of hyperglycemia and lipid metabolism is pivotal for the treatment of type 2 diabetes mellitus (T2DM). Metformin hydrochloride (DMBG) remains the most widely prescribed medication for this condition. This study aimed to elucidate the effects and underlying mechanisms by which DMBG enhances glucolipid metabolism using both in vivo and in vitro experimental models. Animal models were established using high-fat diet (HFD)-fed mice, while cellular models utilized palmitic acid (PA)-induced HepG2 cells. In vivo, the impact of DMBG on glucolipid metabolism was evaluated through measurements of insulin and HbA1c levels, intraperitoneal glucose tolerance tests (ipGTT), intraperitoneal insulin tolerance tests (ipITT), as well as histological assessments with hematoxylin-eosin (HE) and Oil-red O staining. Mitochondrial function was assessed via biochemical assays of TBARS, SOD, ATP, and H2O2 levels in liver tissue, alongside determinations of mitochondrial membrane potential, ROS production, mtDNA content, and SIRT5 mRNA expression. For in vitro analysis, glucose consumption, mitochondrial membrane potential, ROS levels, and protein expressions of AMPK and PGC-1α were quantified in HepG2 cells. Western blotting and co-immunoprecipitation (co-IP) techniques were employed to investigate the mechanistic pathways involved. Treatment with DMBG resulted in reduced levels of free fatty acids, body weight, and fat mass, while also alleviating hyperglycemia and hepatic lipid accumulation in HFD-fed mice. Furthermore, DMBG restored impaired mitochondrial function in these animals and increased SIRT5 expression via AMPK activation. In vitro, DMBG mitigated PA-induced alterations in glucose consumption and mitochondrial dysfunction in HepG2 cells, an effect that was abrogated upon SIRT5 knockdown. Overexpression of SIRT5 led to enhanced trifunctional enzyme subunit-alpha (ECHA) desuccinylation at the K540 site, thereby increasing its activity. Collectively, our findings indicate that DMBG improves hepatic glucolipid metabolism through a mechanism involving SIRT5-mediated ECHA desuccinylation, potentially offering a new therapeutic avenue for T2DM.

Dataset Information

Repression of p53 function by SIRT5-mediated desuccinylation at Lysine 120 in response to DNA damage.

Publications

Repression of p53 function by SIRT5-mediated desuccinylation at Lysine 120 in response to DNA damage.

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