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Nucleic Acids Research 2005 33(9):3057-3064; doi:10.1093/nar/gki612
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Published online 25 May 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oupjournals.org

Article

5-Halogenated pyrimidine lesions within a CpG sequence context mimic 5-methylcytosine by enhancing the binding of the methyl-CpG-binding domain of methyl-CpG-binding protein 2 (MeCP2)

Victoria Valinluck1, Pingfang Liu1,2, Joseph I. Kang, Jr1, Artur Burdzy1 and Lawrence C. Sowers1,2,*

1Department of Biochemistry and Microbiology, School of Medicine, Loma Linda University Loma Linda, CA 92350, USA 2Graduate School of Biological Sciences, City of Hope National Medical Center 1500 East Duarte Road, Duarte, CA 91010, USA

*To whom correspondence should be addressed. Tel: +1 909 558 4480; Fax: +1 909 558 4035; Email: lsowers{at}som.llu.edu

Received April 19, 2005. Accepted May 4, 2005.

Perturbations in cytosine methylation signals are observed in the majority of human tumors; however, it is as yet unknown how methylation patterns become altered. Epigenetic changes can result in the activation of transforming genes as well as in the silencing of tumor suppressor genes. We report that methyl-CpG-binding proteins (MBPs), specific for methyl-CpG dinucleotides, bind with high affinity to halogenated pyrimidine lesions, previously shown to result from peroxidase-mediated inflammatory processes. Emerging data suggest that the initial binding of MBPs to methyl-CpG sequences may be a seeding event that recruits chromatin-modifying enzymes and DNA methyltransferase, initiating a cascade of events that result in gene silencing. MBD4, a protein with both methyl-binding and glycosylase activity demonstrated repair activity against a series of 5-substituted pyrimidines, with the greatest efficiency against 5-chlorouracil, but undetectable activity against 5-chlorocytosine. The data presented here suggest that halogenated pyrimidine damage products can potentially accumulate and mimic endogenous methylation signals.

Present address: Pingfang Liu, Department of Genetics and Complex Disease, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA


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