title: Histone deacetylase SIRT1 modulates and deacetylates DNA base excision repair enzyme thymine DNA glycosylase.
abstract: TDG (thymine DNA glycosylase) is an essential multifunctional enzyme involved in DNA base excision repair, DNA demethylation and transcription regulation. TDG is the predominant enzyme that removes thymine from T/G mispair, which arises due to deamination of 5-methyl-cytosine at the CpG dinucleotide, thereby preventing C to T mutations. SIRT1 is a member of class III NAD+-dependent histone/protein deacetylases. In the present study, we demonstrate that SIRT1 interacts with residues 67-110 of hTDG (human TDG). In addition, SIRT1 enhances TDG glycosylase activity and deacetylates acetylated TDG. TDG acetylation weakens its interaction with SIRT1. Although acetylated TDG has reduced glycosylase activity towards T/G, 5-formylcytosine/G and 5-carboxylcytosine/G, it has a stronger activity towards a 5-fluorouracil/G substrate as compared with unmodified TDG. SIRT1 weakly stimulates acetylated hTDG activity towards T/G, 5-formylcytosine/G and 5-carboxylcytosine/G as compared with control hTDG. Sirt1-knockout mouse embryonic fibroblast cells have higher levels of TDG expression and acetylation. The physical and functional interactions between SIRT1 and TDG may mediate DNA repair, gene expression and FU (5-fluorouracil)-mediated cytotoxicity.
authors: *Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
authors: Amrita
authors: A
authors: Madabushi
authors: Bor-Jang
authors: BJ
authors: Hwang
authors: Jin
authors: J
authors: Jin
authors: A-Lien
authors: AL
authors: Lu
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D004260:DNA Repair; D005347:Fibroblasts / Q000378:metabolism; D005472:Fluorouracil / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D056564:Sirtuin 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D044502:Thymine DNA Glycosylase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D044502:Thymine DNA Glycosylase; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005472:Fluorouracil
references: J Biol Chem. 2011 Oct 14;286(41):35334-35338
references: 21862836
references: PLoS Biol. 2009 Apr 28;7(4):e91
references: 19402749
references: Cell Death Differ. 2001 Nov;8(11):1076-92
references: 11687886
references: Pharmacol Res. 2010 Jul;62(1):35-41
references: 20026274
references: Cell. 2011 Jul 8;146(1):67-79
references: 21722948
references: J Biol Chem. 1995 Oct 6;270(40):23582-8
references: 7559523
references: Exp Mol Med. 2007 Feb 28;39(1):8-13
references: 17334224
references: Mol Cell Biol. 2006 Jan;26(1):28-38
references: 16354677
references: Int J Biol Sci. 2009;5(2):147-52
references: 19173036
references: Mol Cell Biol. 2009 Aug;29(15):4116-29
references: 19470756
references: Biochem J. 2007 May 15;404(1):1-13
references: 17447894
references: Hum Genet. 1988 Feb;78(2):151-5
references: 3338800
references: FEBS Lett. 2000 Jun 30;476(1-2):73-7
references: 10878254
references: Nature. 2011 Feb 17;470(7334):419-23
references: 21278727
references: Cell. 2008 Nov 28;135(5):907-18
references: 19041753
references: Cancer Cell. 2008 Oct 7;14(4):312-23
references: 18835033
references: J Biol Chem. 2008 Nov 21;283(47):32680-90
references: 18805789
references: Cell. 2011 Sep 16;146(6):866-72
references: 21925312
references: Science. 2011 Sep 2;333(6047):1303-7
references: 21817016
references: Cell. 2011 Apr 29;145(3):423-34
references: 21496894
references: Cancer Metastasis Rev. 2008 Jun;27(2):315-34
references: 18246412
references: Annu Rev Pathol. 2010;5:253-95
references: 20078221
references: Annu Rev Biochem. 2004;73:417-35
references: 15189148
references: Nature. 2010 Feb 25;463(7284):1042-7
references: 20027182
references: Prog Nucleic Acid Res Mol Biol. 2001;68:235-53
references: 11554300
references: Mol Cell. 2007 Jul 6;27(1):149-62
references: 17612497
references: Nature. 2008 Mar 6;452(7183):112-5
references: 18322535
references: Nucleic Acids Res. 2010 Jan;38(3):832-45
references: 19934257
references: J Biol Chem. 2009 Jul 3;284(27):18210-7
references: 19433578
references: Cell. 2007 Feb 23;128(4):683-92
references: 17320506
references: Cancer Lett. 2011 Jan 28;300(2):197-204
references: 21067862
references: Cancer Lett. 2011 Jul 1;306(1):10-4
references: 21414717
references: Nucleic Acids Res. 2003 May 1;31(9):2261-71
references: 12711670
references: Curr Biol. 2005 Apr 12;15(7):616-23
references: 15823533
references: Cell. 2010 Sep 17;142(6):930-42
references: 20850014
references: Nat Rev Mol Cell Biol. 2003 Apr;4(4):276-84
references: 12671650
references: Nature. 2008 Mar 6;452(7183):45-50
references: 18322525
references: Cell Metab. 2005 Jul;2(1):67-76
references: 16054100
references: J Biol Chem. 2007 Sep 21;282(38):27578-86
references: 17602166
references: Nucleic Acids Res. 2007;35(18):6207-18
references: 17855402
references: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10794-9
references: 12960381
references: DNA Repair (Amst). 2007 Apr 1;6(4):489-504
references: 17116428
references: Mol Cell. 2010 Jul 30;39(2):247-58
references: 20670893
references: Nat Rev Cancer. 2003 May;3(5):330-8
references: 12724731
references: J Biol Chem. 2004 Dec 10;279(50):52353-60
references: 15448152
references: Nat Rev Mol Cell Biol. 2010 Sep;11(9):607-20
references: 20683471
references: Mol Cell. 2002 Feb;9(2):265-77
references: 11864601
references: Nucleic Acids Res. 2010 Mar;38(4):1135-48
references: 19966277
references: J Biol Chem. 1999 Jan 1;274(1):67-74
references: 9867812
references: Cell. 2006 Jan 27;124(2):315-29
references: 16439206
references: J Am Chem Soc. 2006 Sep 27;128(38):12510-9
references: 16984202