Acetyl-CoA is a central node in carbon metabolism and plays critical roles in regulatory and biosynthetic processes. The acetyl-CoA synthetase Acs2, which catalyses acetyl-CoA production from acetate, is an integral subunit of the serine-responsive SAM-containing metabolic enzyme (SESAME) complex, but the precise function of Acs2 within the SESAME complex remains unclear. Here, using budding yeast, we show that Acs2 within the SESAME complex is required for the regulation of telomere silencing and cellular senescence. Mechanistically, the SESAME complex interacts with the histone acetyltransferase SAS protein complex to promote histone H4K16 acetylation (H4K16ac) enrichment and the occupancy of bromodomain-containing protein, Bdf1, at subtelomeric regions. This interaction maintains telomere silencing by antagonizing the spreading of Sir2 along the telomeres, which is enhanced by acetate. Consequently, dissociation of Sir2 from telomeres by acetate leads to compromised telomere silencing and accelerated chronological ageing. In human endothelial cells, ACSS2, the ortholog of yeast Acs2, also interacts with H4K16 acetyltransferase hMOF and are required for acetate to increase H4K16ac, reduce telomere silencing and induce cell senescence. Altogether, our results reveal a conserved mechanism to connect cell metabolism with telomere silencing and cellular senescence.
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Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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Site | Modification | Modifier | Source | Reference |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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