Abstract
This study focuses on understanding the role of c-Myc, a cancer-associated transcription factor, in the penumbra following ischemic stroke. While its involvement in cell death and survival is recognized, its post-translational modifications, particularly acetylation, remain understudied in ischemia models. Investigating these modifications could have significant clinical implications for controlling c-Myc activity in the central nervous system. Although previous studies on c-Myc acetylation have been limited to non-neuronal cells, our research examines its expression in perifocal cells during stroke recovery to explore regulatory mechanisms via acetylation. We found that in peri-infarct neurons, c-Myc is upregulated with acetylation at K148 but not K323 during the acute phase of stroke, with SIRT2 deacetylase primarily affecting K148 acetylation. Molecular dynamics simulations suggest that lysine 148 plays a crucial role in stabilizing c-Myc spatial structure. Increased acetylation at K148 reduces c-Myc compaction, potentially limiting its nuclear penetration, promoting calpain-mediated cleavage, and decreasing nuclear localization. Additionally, cytoplasmic acetylation at K148 may alter c-Myc's interaction with unidentified proteins, potentially influencing its pro-apoptotic effects and promoting cytoplasmic accumulation. Targeting SIRT2 with selective inhibitors could be a promising avenue for future stroke therapy strategies.
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The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
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This work was supported by the Ministry of Science and Higher Education of the Russian Federation (Grant number FENW-2023–0018).
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Guzenko V.V. contributed toward investigation. Bachurin S.S. contributed toward methodology, investigation, formal analysis, visualization, and writing—original draft. Khaitin A.M. contributed toward investigation, formal analysis, visualization, and writing—review & editing. Dzreyan V.A. contributed toward investigation. Kalyuzhnaya Y.N. contributed toward investigation. Demyanenko S.V. contributed toward investigation, visualization, project administration, supervision, conceptualization, methodology, funding acquisition, and writing—original draft.
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Guzenko, V.V., Bachurin, S.S., Dzreyan, V.A. et al. Acetylation of c-Myc at Lysine 148 Protects Neurons After Ischemia. Neuromol Med 26, 8 (2024). https://doi.org/10.1007/s12017-024-08777-2
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DOI: https://doi.org/10.1007/s12017-024-08777-2