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Nucleic Acids Res. 2010 Jul;38(13):4313-24. doi: 10.1093/nar/gkq187. Epub 2010 Mar 25.

Targeting of 5-aza-2'-deoxycytidine residues by chromatin-associated DNMT1 induces proteasomal degradation of the free enzyme.

Author information

1
Breakthrough Research Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Abstract

5-Aza-2'-deoxycytidine (5-aza-dC) is a nucleoside analogue with cytotoxic and DNA demethylating effects. Here we show that 5-aza-dC induces the proteasomal degradation of free (non-chromatin bound) DNMT1 through a mechanism which is dependent on DNA synthesis and the targeting of incorporated 5-aza-dC residues by DNMT1 itself. Thus, 5-aza-dC induces Dnmt1 degradation in wild-type mouse ES cells, but not in Dnmt [3a(-/-), 3b(-/-)] mouse ES cells which express Dnmt1 but lack DNA methylation (<0.7% of CpG methylated) and contain few hemi-methylated CpG sites, these being the preferred substrates for Dnmt1. We suggest that adducts formed between DNMT1 and 5-aza-dC molecules in DNA induce a ubiquitin-E3 ligase activity which preferentially targets free DNMT1 molecules for degradation by the proteasome. The proteasome inhibitor MG132 prevents DNMT1 degradation and reduces hypomethylation induced by 5-aza-dC.

PMID:
20348135
PMCID:
PMC2910061
DOI:
10.1093/nar/gkq187
[Indexed for MEDLINE]
Free PMC Article

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