DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination

Du, Z., Song, J., Wang, Y., Zhao, Y., Guda, K., Yang, S., Kao, H.-Y., Xu, Y., Willis, J., Markowitz, S. D., Sedwick, D., Ewing, R. M. and Wang, Z. (2010) DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination. Science Signaling, 3, (146), p.ra80. (doi:10.1126/scisignal.2001462). (PMID:21045206).


[img] PDF - Abstract
Download (58Kb)


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.

Item Type: Article
Digital Object Identifier (DOI): doi:10.1126/scisignal.2001462
ISSNs: 1937-9145 (print)
Related URLs:
Subjects: T Technology > T Technology (General)
Divisions : Faculty of Natural and Environmental Sciences
Faculty of Natural and Environmental Sciences > Biological Sciences
ePrint ID: 340656
Accepted Date and Publication Date:
November 2010Published
Date Deposited: 28 Jun 2012 09:44
Last Modified: 31 Mar 2016 14:30
URI: http://eprints.soton.ac.uk/id/eprint/340656

Actions (login required)

View Item View Item

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics