DNA methyltransferase 1 (DNMT1) is the primary enzyme that maintains DNA 
methylation. We describe a previously unknown mode of regulation of DNMT1 
protein stability through the coordinated action of an array of DNMT1-associated 
proteins. DNMT1 was destabilized by acetylation by the acetyltransferase Tip60, 
which triggered ubiquitination by the E3 ligase UHRF1, thereby targeting DNMT1 
for proteasomal degradation. In contrast, DNMT1 was stabilized by histone 
deacetylase 1 (HDAC1) and the deubiquitinase HAUSP (herpes virus-associated 
ubiquitin-specific protease). Analysis of the abundance of DNMT1 and Tip60, as 
well as the association between HAUSP and DNMT1, suggested that during the cell 
cycle the initiation of DNMT1 degradation was coordinated with the end of DNA 
replication and the need for DNMT activity. In human colon cancers, the 
abundance of DNMT1 correlated with that of HAUSP. HAUSP knockdown rendered colon 
cancer cells more sensitive to killing by HDAC inhibitors both in tissue culture 
and in tumor xenograft models. Thus, these studies provide a mechanism-based 
rationale for the development of HDAC and HAUSP inhibitors for combined use in 
cancer therapy.