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

DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination
DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination
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.
p.ra80
Du, Z.
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Song, J.
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Wang, Y.
23c775f0-3cac-44d5-9e16-2098959c493b
Zhao, Y.
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Guda, K.
38750571-0b1c-44cf-94ed-8ab2cd6ae9e1
Yang, S.
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Kao, H.-Y.
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Xu, Y.
30b17987-352d-4c0e-b58b-25c03dcd223d
Willis, J.
8d00cdf0-48e2-40e9-8a7b-45d29b249e87
Markowitz, S. D.
e2c6e289-9a94-4b3c-8957-a921c41325fa
Sedwick, D.
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Ewing, R. M.
022c5b04-da20-4e55-8088-44d0dc9935ae
Wang, Z.
8983928f-aca4-4b48-a71b-959646c6aa77
Du, Z.
5e06020e-efcb-46a3-8947-05b86da707be
Song, J.
e82ff981-9c67-4ff5-8971-cb518bd1b3db
Wang, Y.
23c775f0-3cac-44d5-9e16-2098959c493b
Zhao, Y.
d6302903-ff65-45d3-b16b-ccab58d5d835
Guda, K.
38750571-0b1c-44cf-94ed-8ab2cd6ae9e1
Yang, S.
b5909d57-37ad-487f-921e-2bbbe6870b76
Kao, H.-Y.
3df25f01-6d76-44e4-8c99-5b7500733b87
Xu, Y.
30b17987-352d-4c0e-b58b-25c03dcd223d
Willis, J.
8d00cdf0-48e2-40e9-8a7b-45d29b249e87
Markowitz, S. D.
e2c6e289-9a94-4b3c-8957-a921c41325fa
Sedwick, D.
4f313855-4ab8-4f13-ba5c-80dd48d1e8df
Ewing, R. M.
022c5b04-da20-4e55-8088-44d0dc9935ae
Wang, Z.
8983928f-aca4-4b48-a71b-959646c6aa77

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

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Date deposited: 28 Jun 2012 09:44
Last modified: 03 Dec 2019 01:37

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