Abstract
Sirtuin6 (SIRT6) has been implicated as a key factor in aging and aging-related diseases. However, the role of SIRT6 in cellular senescence has not been fully understood. Here, we show that SIRT6 repressed the expression of p27Kip1 (p27) in cellular senescence. The expression of SIRT6 was reduced during cellular senescence, whereas enforced SIRT6 expression promoted cell proliferation and antagonized cellular senescence. In addition, we demonstrated that SIRT6 promoted p27 degradation by proteasome and SIRT6 decreased the acetylation level and protein half-life of p27. p27 acetylation increased its protein stability. Furthermore, SIRT6 directly interacted with p27. Importantly, p27 was strongly acetylated and had a prolonged protein half-life with the reduction of SIRT6 when cells were senescent, compared with those young cells. Finally, SIRT6 markedly rescued senescence induced by p27. Our findings indicate that SIRT6 decreases p27 acetylation, leading to its degradation via ubiquitin-proteasome pathway and then delays cellular senescence.
Highlights
Sirtuins are highly conserved NAD+-dependent deacylases and/or mono-ADP-ribosyltransferase that have been shown to regulate lifespan in several organisms [1]
Our findings indicate that SIRT6 decreases p27 acetylation, leading to its degradation via ubiquitin‐proteasome pathway and delays cellular senescence
Expression of SIRT6 is decreased during senescence in human fibroblasts
Summary
Sirtuins are highly conserved NAD+-dependent deacylases and/or mono-ADP-ribosyltransferase that have been shown to regulate lifespan in several organisms [1]. SIRT6 is predominantly located in the nucleus [7, 11] and belongs to the class IV sirtuins, displays deacylase and ADP-ribosyltransferase activities [9, 10]. These seven proteins play key roles in a wide variety of cellular and physiological processes such as cell proliferation, differentiation, genome stability, metabolism, energy homeostasis, aging and cancer [11,12,13,14,15]. SIRT6-deficient mice are small and develop several acute degenerative processes that include profound lymphopenia, loss of subcutaneous fat, lordokyphosis, and severe metabolic defects at 2-3 weeks of age. Subsequent studies link SIRT6 with genomic stability, DNA repair, glucose metabolism, cancer, lipid metabolism, inflammation and heart disease [17,18,19,20,21,22,23,24,25]
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