title: SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities.
abstract: DNA methylation and histone acetylation/deacetylation are distinct biochemical processes that control gene expression. While DNA methylation is a common epigenetic signal that inhibits gene transcription, histone deacetylation similarly represses transcription but can be both an epigenetic and nonepigenetic phenomenon. Here we report that the histone deacetylase SIRT1 regulates the activities of DNMT1, a key enzyme responsible for DNA methylation. In mass spectrometry analysis, 12 new acetylated lysine sites were identified in DNMT1. SIRT1 physically associates with DNMT1 and can deacetylate acetylated DNMT1 in vitro and in vivo. Interestingly, deacetylation of different lysines on DNMT1 has different effects on the functions of DNMT1. For example, deacetylation of Lys1349 and Lys1415 in the catalytic domain of DNMT1 enhances DNMT1's methyltransferase activity, while deacetylation of lysine residues in the GK linker decreases DNMT1's methyltransferase-independent transcriptional repression function. Furthermore, deacetylation of all identified acetylated lysine sites in DNMT1 abrogates its binding to SIRT1 and impairs its capability to regulate cell cycle G(2)/M transition. Finally, inhibition of SIRT1 strengthens the silencing effects of DNMT1 on the expression of tumor suppressor genes ER-α and CDH1 in MDA-MB-231 breast cancer cells. Together, these results suggest that SIRT1-mediated deacetylation of DNMT1 is crucial for DNMT1's multiple effects in gene silencing.
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
authors.forename: Lirong
authors.initials: L
authors.lastname: Peng
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yuan
authors.forename: Hongbo
authors.initials: H
authors.lastname: Ling
authors.forename: Kenji
authors.initials: K
authors.lastname: Fukasawa
authors.forename: Keith
authors.initials: K
authors.lastname: Robertson
authors.forename: Nancy
authors.initials: N
authors.lastname: Olashaw
authors.forename: John
authors.initials: J
authors.lastname: Koomen
authors.forename: Jiandong
authors.initials: J
authors.lastname: Chen
authors.forename: William S
authors.initials: WS
authors.lastname: Lane
authors.forename: Edward
authors.initials: E
authors.lastname: Seto
mesh_terms: D000107:Acetylation; D000818:Animals; D059447:Cell Cycle Checkpoints; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D057075:Enzyme Assays; D015870:Gene Expression; D005786:Gene Expression Regulation; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D007700:Kinetics; D051379:Mice; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D034622:RNA Interference; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D056572:Histone Deacetylase Inhibitors; D056564:Sirtuin 1; D025521:Tumor Suppressor Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C447939:SIRT1 protein, human