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

Rebecca L Fagan; Diane E Cryderman; Levy Kopelovich; Lori L Wallrath; Charles Brenner

doi:10.1074/jbc.M113.480517

Back

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

Journal article

Open access

Peer reviewed

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

Rebecca L Fagan, Diane E Cryderman, Levy Kopelovich, Lori L Wallrath and Charles Brenner

The Journal of biological chemistry, Vol.288(33), pp.23858-23867

08/16/2013

DOI: 10.1074/jbc.M113.480517

PMCID: PMC3745332

PMID: 23839987

Files and links (1)

url

https://doi.org/10.1074/jbc.M113.480517View

Published (Version of record) Open Access

Abstract

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.

Oligonucleotide Array Sequence Analysis

DNA Replication - drug effects

Humans

Azacitidine - chemistry

Molecular Sequence Data

DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors

Fluorometry

Pyrimidines - chemistry

Azo Compounds - chemistry

DNA (Cytosine-5-)-Methyltransferases - metabolism

Breast Neoplasms - enzymology

MCF-7 Cells

Base Sequence

Enzyme Inhibitors - chemistry

Female

Gene Expression Regulation, Neoplastic - drug effects

Aminoquinolines - pharmacology

Azo Compounds - pharmacology

Reproducibility of Results

Enzyme Inhibitors - pharmacology

Azacitidine - analogs & derivatives

DNA Methylation - genetics

Signal Transduction - genetics

DNA - metabolism

Pyrimidines - pharmacology

Azacitidine - pharmacology

Breast Neoplasms - genetics

Signal Transduction - drug effects

Aminoquinolines - chemistry

Anthraquinones - pharmacology

DNA Methylation - drug effects

Transition Temperature

Details

Title: Subtitle: Laccaic acid A is a direct, DNA-competitive inhibitor of DNA methyltransferase 1
Creators: Rebecca L Fagan - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
Diane E Cryderman
Levy Kopelovich
Lori L Wallrath
Charles Brenner
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.288(33), pp.23858-23867
DOI: 10.1074/jbc.M113.480517
PMID: 23839987
PMCID: PMC3745332
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: R01 CA075954 / NCI NIH HHS R01CA075954 / NCI NIH HHS HHSN261200433000C / PHS HHS
Language: English
Date published: 08/16/2013
Academic Unit: Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9983788429902771

Metrics

24 Record Views

62 Times Cited - Web of Science