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J Biol Chem. 2013 Aug 16;288(33):23858-67. doi: 10.1074/jbc.M113.480517. Epub 2013 Jul 9.

Laccaic acid A is a direct, DNA-competitive inhibitor of DNA methyltransferase 1.

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Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.


Methylation of cytosines in CpG dinucleotides is the predominant epigenetic mark on vertebrate DNA. DNA methylation is associated with transcriptional repression. The pattern of DNA methylation changes during development and with disease. Human DNA methyltransferase 1 (Dnmt1), a 1616-amino acid multidomain enzyme, is essential for maintenance of DNA methylation in proliferating cells and is considered an important cancer drug target. Using a fluorogenic, endonuclease-coupled DNA methylation assay with an activated form of Dnmt1 engineered to lack the replication foci targeting sequence domain, we discovered that laccaic acid A (LCA), a highly substituted anthraquinone natural product, is a direct inhibitor with a 310 nm Ki. LCA is competitive with the DNA substrate in in vitro methylation assays and alters the expression of methylated genes in MCF-7 breast cancer cells synergistically with 5-aza-2'-deoxycytidine. LCA represents a novel class of Dnmt-targeted molecular probes, with biochemical properties that allow it to distinguish between non DNA-bound and DNA-bound Dnmt1.


Cancer Therapy; Chemical Biology; DNA Methylation; DNA Methyltransferase; Drug Action; Drug Discovery; Enzyme Inhibitors; Fret; Gene Silencing; Microarray

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