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.