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.

乙酰辅酶A是碳代谢的中心节点，在调节和生物合成过程中发挥着关键作用。乙酰辅酶 A 合成酶 Acs2 催化乙酸盐生成乙酰辅酶 A，它是丝氨酸响应性 SAM 代谢酶 (SESAME) 复合物的一个组成部分，但 Acs2 在 SESAME 复合物中的精确功能仍不清楚。在这里，我们使用芽殖酵母证明 SESAME 复合体中的 Acs2 对于端粒沉默和细胞衰老的调节是必需的。从机制上讲，SESAME 复合物与组蛋白乙酰转移酶 SAS 蛋白复合物相互作用，促进组蛋白 H4K16 乙酰化 (H4K16ac) 富集以及含溴结构域蛋白 Bdf1 在亚端粒区域的占据。这种相互作用通过拮抗 Sir2 沿着端粒的扩散来维持端粒沉默，而醋酸盐可以增强这种作用。因此，乙酸盐使 Sir2 从端粒解离会导致端粒沉默受损并加速老化。在人内皮细胞中，酵母 Acs2 的直系同源物 ACSS2 也与 H4K16 乙酰转移酶 hMOF 相互作用，并且是乙酸盐增加 H4K16ac、减少端粒沉默和诱导细胞衰老所必需的。总而言之，我们的结果揭示了一种将细胞代谢与端粒沉默和细胞衰老联系起来的保守机制。