CK2 is the regulator of SIRT1 substrate-binding affinity, deacetylase activity and cellular response to DNA-damage.
SIRT1, an NAD(+) (nicotinamide adenine dinucleotide)-dependent deacetylase, protects cells from stress-induced apoptosis, and its orthologues delay aging in lower eukaryotes. SIRT1 increases survival in response to stress such as DNA damage by deacetylating a number of substrates including pro-apoptotic protein p53. The molecular mechanism by which DNA-damage activates SIRT1 is not known. By screening a kinase inhibitor library, we identified CK2 as a SIRT1 kinase. CK2 is a pleiotropic kinase with more than 300 substrates and well-known anti-apoptotic and pro-growth activities. We find that CK2 is recruited to SIRT1 after ionizing radiation (IR) and phosphorylates conserved residues Ser 154, 649, 651 and 683 in the N- and C-terminal domains of mouse SIRT1. Phosphorylation of SIRT1 increases its deacetylation rate but not if the four Ser residues are mutated. In addition, phosphorylation of SIRT1 increases its substrate-binding affinity. CK2-mediated phosphorylation increases the ability of SIRT1 to deacetylate p53 and protect cells from apoptosis after DNA damage. Based on these findings, we propose that CK2 protects against IR-induced apoptosis partly by phosphorylating and activating SIRT1. Thus, this work suggests that SIRT1 is a component of the expansive anti-apoptotic network controlled by CK2. Since expression of both CK2 and SIRT1 is upregulated with tumorigenesis and downregulated with senescence, the CK2-SIRT1 link sheds new light on how CK2 may regulate cancer development and aging.
Kang
Hyeog
H
Laboratory of Biochemical Genetics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Jung
Jae-Won
JW
Kim
Myung K
MK
Chung
Jay H
JH
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D047390:Casein Kinase II / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage; D015536:Down-Regulation; D047468:Immunoprecipitation; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017386:Sequence Homology, Amino Acid; D056564:Sirtuin 1 / Q000737:chemistry / Q000502:physiology*; D013379:Substrate Specificity
D047390:Casein Kinase II; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
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