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)

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 th...

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Bibliographic Details
Published in:Nucleic acids research 2005-01, Vol.33 (9), p.3057-3064
Main Authors: Valinluck, Victoria, Liu, Pingfang, Kang, Joseph I., Burdzy, Artur, Sowers, Lawrence C.
Format: Article
Language:English
Subjects:
5-Methylcytosine - chemistry
Animals
Binding Sites
Chromosomal Proteins, Non-Histone - chemistry
Chromosomal Proteins, Non-Histone - metabolism
CpG Islands
DNA Damage
DNA Glycosylases - metabolism
DNA Methylation
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - metabolism
Electrophoretic Mobility Shift Assay
Endodeoxyribonucleases - metabolism
Halogens - chemistry
Humans
Methyl-CpG-Binding Protein 2
Mice
Protein Binding
Protein Structure, Tertiary
Pyrimidines - chemistry
Repressor Proteins - chemistry
Repressor Proteins - metabolism
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gki612