title: CK2 is the regulator of SIRT1 substrate-binding affinity, deacetylase activity and cellular response to DNA-damage.
abstract: 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.
authors.affiliation: Laboratory of Biochemical Genetics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Hyeog
authors.initials: H
authors.lastname: Kang
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Jung
authors.forename: Myung K
authors.initials: MK
authors.lastname: Kim
authors.forename: Jay H
authors.initials: JH
authors.lastname: Chung
mesh_terms: 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
chemical_list: D047390:Casein Kinase II; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
references.citation: Genes Dev. 2006 Nov 1;20(21):2913-21
references.pmid: 17079682
references.citation: J Cell Sci. 2002 Oct 15;115(Pt 20):3873-8
references.pmid: 12244125
references.citation: Cell. 1997 Aug 22;90(4):595-606
references.pmid: 9288740
references.citation: Trends Cell Biol. 2002 May;12(5):226-30
references.pmid: 12062170
references.citation: Cell Tissue Res. 2000 Sep;301(3):329-40
references.pmid: 10994779
references.citation: EMBO J. 1990 Oct;9(10):3253-60
references.pmid: 2145148
references.citation: Nature. 2008 Jan 31;451(7178):583-6
references.pmid: 18235501
references.citation: FEBS Lett. 2004 Jan 2;556(1-3):281-6
references.pmid: 14706864
references.citation: Int J Cancer. 2008 Jan 15;122(2):333-41
references.pmid: 17935135
references.citation: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6399-402
references.pmid: 9600977
references.citation: Biochim Biophys Acta. 2008 Jan;1784(1):33-47
references.pmid: 17931986
references.citation: J Biol Chem. 2007 Mar 2;282(9):6823-32
references.pmid: 17197703
references.citation: Proc Natl Acad Sci U S A. 1990 Jan;87(2):821-5
references.pmid: 2300566
references.citation: Chembiochem. 2007 Jan 2;8(1):129-39
references.pmid: 17133643
references.citation: Cancer Res. 2005 May 15;65(10):4362-7
references.pmid: 15899828
references.citation: PLoS One. 2008 Apr 16;3(4):e2020
references.pmid: 18414679
references.citation: Cancer Cell. 2008 Oct 7;14(4):312-23
references.pmid: 18835033
references.citation: EMBO J. 2004 Jun 16;23(12):2369-80
references.pmid: 15152190
references.citation: Cell. 1992 Nov 27;71(5):875-86
references.pmid: 1423635
references.citation: J Biol Chem. 1989 May 5;264(13):7345-8
references.pmid: 2708368
references.citation: J Biol Chem. 1999 May 14;274(20):14406-14
references.pmid: 10318865
references.citation: Mol Cell. 2007 Oct 26;28(2):277-90
references.pmid: 17964266
references.citation: Prog Nucleic Acid Res Mol Biol. 1998;59:95-133
references.pmid: 9427841
references.citation: Cell. 1990 Nov 16;63(4):751-62
references.pmid: 2225075
references.citation: Genes Dev. 1998 Sep 15;12(18):2831-41
references.pmid: 9744860
references.citation: Nature. 2008 Jan 31;451(7178):587-90
references.pmid: 18235502
references.citation: Science. 2004 Jul 16;305(5682):390-2
references.pmid: 15205477
references.citation: Mol Cell. 2001 Feb;7(2):283-92
references.pmid: 11239457
references.citation: Cell. 2001 Oct 19;107(2):149-59
references.pmid: 11672523
references.citation: Cell. 2005 Nov 4;123(3):437-48
references.pmid: 16269335
references.citation: Biochem Biophys Res Commun. 1999 Jun 24;260(1):273-9
references.pmid: 10381378
references.citation: Cell. 2001 Oct 19;107(2):137-48
references.pmid: 11672522
references.citation: Nature. 2000 Feb 17;403(6771):795-800
references.pmid: 10693811
references.citation: Cell. 1997 Dec 26;91(7):1033-42
references.pmid: 9428525
references.citation: Nat Cell Biol. 2007 Nov;9(11):1253-62
references.pmid: 17934453
references.citation: PLoS One. 2008;3(12):e4020
references.pmid: 19107194
references.citation: Cancer Res. 2007 Jul 15;67(14):6612-8
references.pmid: 17638871
references.citation: Aging Cell. 2006 Oct;5(5):413-22
references.pmid: 16939484
references.citation: FEBS Lett. 2006 Feb 6;580(3):988-94
references.pmid: 16442104
references.citation: Mol Cell Biol. 2003 Jan;23(1):38-54
references.pmid: 12482959
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10794-9
references.pmid: 12960381
references.citation: Genetics. 1987 May;116(1):9-22
references.pmid: 3297920
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2834-7
references.pmid: 9501176
references.citation: Nature. 2005 Mar 3;434(7029):113-8
references.pmid: 15744310
references.citation: Biochem J. 2003 Jan 1;369(Pt 1):1-15
references.pmid: 12396231
references.citation: Biochem Biophys Res Commun. 2009 Apr 10;381(3):372-7
references.pmid: 19236849
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):5807-11
references.pmid: 10811920
references.citation: J Cell Physiol. 2007 Oct;213(1):88-97
references.pmid: 17516504
references.citation: EMBO J. 2002 May 15;21(10):2383-96
references.pmid: 12006491
references.citation: J Biol Chem. 2005 Dec 2;280(48):40364-74
references.pmid: 16183991