AVE 0991 br Introduction Cellular senescence is characterize

Introduction Cellular senescence is characterized by irreversible cell proliferation arrest that is triggered by several stimuli including telomere attrition, oxidative stress, and oncogenic activation. In vivo, senescence is thought to act as an important tumor suppression mechanism to eliminate dangerous cells and has also been suggested to cause tissue aging by exhausting renewable tissue stem cells [1,2]. Senescent cells have several molecular features and cytological markers: a large flat morphology, senescence-associated β-galactosidase activity (SA-β-gal), activation of the p53 and p21Cip1/WAF1 axis, senescence-associated secretory phenotype, and senescence-associated heterochromatin foci (SAHF) [[3], [4], [5]]. SAHF, which are visible as distinct DNA foci upon 4′,6-Diamidino-2-phenylindole (DAPI) staining of senescent cells, result from condensation of chromatin into characteristically punctate heterochromatic domains. SAHF formation represses the expression of genes encoding AVE 0991 progression-associated proteins such as cyclin A, proliferating cell nuclear antigen, and cyclin D1. SAHF contain various markers of transcriptionally silent heterochromatin, such as trimethylated histone H3 Lys 9 (H3K9me3) and heterochromatin proteins 1 (HP1α, β, and γ) [[5], [6], [7], [8], [9]]. The total amount of H3K9me3 is increased in the senescent cells and H3K9me3 is repositioned to the nuclear membrane nearby Lamin B [10]. The methylation status of H3K9 can be regulated by specific histone methyltransferases (HMTs) including SUV39h1, G9a, GLP, and SETDB1, as well as histone demethylases including LSD1, JmjD1a, and JmjD2c [11,12]. These HMTs contain a conserved SET domain encoding methyl transferase activity, form a complex together, and cooperate in gene silencing [13]. Among them, G9a and GLP (G9a-like protein) are principally responsible for mono- or di-methylation of H3K9 in euchromatin [14]. SETDB1 alone dimethylates H3K9 but trimethylates this site when associated with mAM [15]. In contrast, SUV39h1 mainly mediates tri-methylation of H3K9 using mono- or di-methylated H3K9 as a primary substrate [16]. However, little is known about the mechanism underlying SAHF formation during cellular senescence. We have previously reported that CK2 is downregulated in senescent human lung fibroblast IMR-90 cells, aged rat tissues, and aging nematodes [17,18]. CK2 downregulation induces cellular senescence via the PI3K-AKT-mTOR-reactive oxygen species-p53-p21Cip1/WAF1 pathway in human cells [[19], [20], [21]]. We have also shown that kin-10 (the Caenorhabditis elegans ortholog of CK2β) knockdown induces age-related biomarkers including reduced longevity and retardation of locomotion in C. elegans [18]. In this study, we examined the physiological significance of CK2 in the context of chromatin reorganization during cellular senescence. Our results indicate, for the first time, that CK2 downregulation stimulates SUV39h1 expression and decreases G9a expression, and this event triggers H3K9 tri-methylation and SAHF formation.