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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).

Record type: Article

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.

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Published date: November 2010
Organisations: Faculty of Natural and Environmental Sciences, Centre for Biological Sciences

Identifiers

Local EPrints ID: 340656
URI: http://eprints.soton.ac.uk/id/eprint/340656
PURE UUID: 818fdd87-0456-4dac-a9ee-8893715200b9
ORCID for R. M. Ewing: ORCID iD orcid.org/0000-0001-6510-4001

Catalogue record

Date deposited: 28 Jun 2012 09:44
Last modified: 18 Jul 2017 05:42

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Contributors

Author: Z. Du
Author: J. Song
Author: Y. Wang
Author: Y. Zhao
Author: K. Guda
Author: S. Yang
Author: H.-Y. Kao
Author: Y. Xu
Author: J. Willis
Author: S. D. Markowitz
Author: D. Sedwick
Author: R. M. Ewing ORCID iD
Author: Z. Wang

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