Document Type

Article

Publication Date

11-2-2010

Publication Title

Science Signaling

Abstract

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.

Comments

This research was supported by the NIH (grants R01-CA127590, R01-HG004722, and HG004722-02S1) and the V foundation (to Z.W.); R01-CA101983 (to D.S.); DK078965 and HL093269 (to H.-Y.K.); and the core facilities of the Case Comprehensive Cancer Center (P30 CA43703).

DOI

10.1126/scisignal.2001462

Version

Postprint

Volume

3

Issue

146

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