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 Valinluck, Pingfang Liu, Joseph I. Kang, Artur Burdzy, Lawrence Sowers

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3057-3064
Number of pages8
JournalNucleic Acids Research
Volume33
Issue number9
DOIs
StatePublished - 2005
Externally publishedYes

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Methyl-CpG-Binding Protein 2
5-Methylcytosine
Methylation
Carrier Proteins
Pyrimidines
Cytosine
Methyltransferases
Gene Silencing
Tumor Suppressor Genes
Oncogenes
Epigenomics
Peroxidase
Chromatin
DNA
Enzymes
Methyl CpG Binding Domain
pyrimidine
Neoplasms
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

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). / Valinluck, Victoria; Liu, Pingfang; Kang, Joseph I.; Burdzy, Artur; Sowers, Lawrence.

In: Nucleic Acids Research, Vol. 33, No. 9, 2005, p. 3057-3064.

Research output: Contribution to journalArticle

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AU - Sowers, Lawrence

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