Resveratrol rescues cutaneous radiation-induced DNA damage via a novel AMPK/SIRT7/HMGB1 regulatory axis

Abstract

Cutaneous radiation injury (CRI) interrupts the scheduled process of radiotherapy and even compromises the life quality of patients. However, the current clinical options for alleviating CRI are relatively limited. Resveratrol (RSV) has been shown to be a promising protective agent against CRI; yet the mechanisms of RSV enhancing radioresistance were not fully elucidated and limited its clinical application. In this study, we demonstrate RSV promotes cutaneous radioresistance mainly through SIRT7. During ionizing radiation (IR) treatment, RSV indirectly phosphorylates and activates SIRT7 through AMPK, which is critical for maintaining the genome stability of keratinocytes. Immunoprecipitation and mass spectrometry identified HMGB1 to be the key interacting partner of SIRT7 to mediate the radioprotective function of RSV. Mechanistic study elucidated that SIRT7 interacts with and deacetylates HMGB1 to redistribute it into nucleus and “switch on” its function for DNA damage repair. Our findings establish a novel AMPK/SIRT7/HMGB1 regulatory axis that mediates the radioprotective function of RSV to alleviate IR-induced cutaneous DNA injury, providing an efficiently-curative option for patients with CRI during radiotherapy.

SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging

“…SIRT7 deacetylation of histones and chromatin regulation has been a key focus, however there is increasing evidence of SIRT7 interacting with transcription factors to elicit transcription programs. For example, SIRT7 suppresses transcription factor HMG box SOX9 in chondrocytes 69 and SIRT7 regulates cellular localization of transcription factor HMGB1 during hepatocyte stellate cell activation 22 . Here, we identified interaction of SIRT7 with the HMG protein NUCKS1 ( Fig.…”

“…The depletion of SIRT7 in human mesenchymal stem cells accelerates senescence and leads to deregulation of heterochromatin and upregulation of LINE-1 elements to initiate the innate immune response 14,15 . While SIRT7 resgulates histone acetylation, SIRT7 also deacetylates non-histone protein targets, including p53 16 , DDB1 17 , CDK9 18 , PCAF 19 , CRY1 20 , NPM1 21 , HMGB1 22 , and has mono-ADP ribosylation activity including self-ribosylation 23 . SIRT7-dependent deacetylation of non-histone targets is critical for mediating the stress response; SIRT7 regulates p53 activity by directly deacetylating the protein itself 16 or regulators of p53 19,21,24 .…”

Acrylamide-induced meiotic arrest of spermatocytes in adolescent mice by triggering excessive DNA strand breaks: Potential therapeutic effects of resveratrol

“…For instance, resveratrol-mediated activation of the AMPK/SIRT7/HMGB1 pathway was involved in protection against radiation-induced cutaneous DNA damage. 54 Resveratrol can also activate SIRT3 and relieve asbestos-induced mitochondrial DNA damage in alveolar epithelial cells in mice. 55 In addition, resveratrol was reported to inhibit the activity of CYP2E1, which plays a critical role in the metabolism of AA to the more genotoxic compound GA.…”

Prevention and Co-Management of Breast Cancer-Related Osteoporosis Using Resveratrol

“…Resveratrol analogs further suppress epigenetic-triggered hypoxia-inducible factor 1-alpha (HIF-1α) and VEGF in BC, thereby sensitizing the effect of radiotherapy effectively through the modulation of the hypoxic state and blood flow under hypoxia conditions, leading to the inhibition of angiogenesis [ 173 ]. Moreover, resveratrol has recently been reported to repair radiation-induced DNA damage in skin tissue via a novel AMPK/Sirt-7/high-mobility-group-box-1 (HMGB1) regulatory axis, underscoring the multifunctional mode of action of resveratrol [ 174 ].…”