Cited by 756Epigenetics and DNA MethylationDNA and Nucleic Acid ChemistryGenomics and Chromatin Dynamics

Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2)

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Valinluck, V.·2004·Nucleic Acids Research

Abstract

Cytosine methylation in CpG dinucleotides is believed to be important in gene regulation, and is generally associated with reduced levels of transcription. Methylation-mediated gene silencing involves a series of DNA-protein and protein-protein interactions that begins with the binding of methyl-CpG binding proteins (MBPs) followed by the recruitment of histone-modifying enzymes that together promote chromatin condensation and inactivation. It is widely known that alterations in methylation patterns, and associated gene activities, are often found in human tumors. However, the mechanisms by which methylation patterns are altered are not currently understood. In this paper, we investigate the impact of oxidative damage to a methyl-CpG site on MBP binding by the selective placement of 8-oxoguanine (8-oxoG) and 5-hydroxymethylcytosine (HmC) in a MBP recognition sequence. Duplexes containing these specific modifications were assayed for binding to the methyl-CpG binding domain (MBD) of one member of the MBP family, methyl-CpG binding protein 2 (MeCP2). Our results reveal that oxidation of either a single guanine to 8-oxoG or of a single 5mC to HmC, significantly inhibits binding of the MBD to the oligonucleotide duplex, reducing the binding affinity by at least an order of magnitude. Oxidative damage to DNA could therefore result in heritable, epigenetic changes in chromatin organization.

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Crossref · 10.1093/nar/gkh739

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  • Repressive MECP2 binding was reduced in areas of DNA hydroxymethylation, likely due to MECP2's lower affinity for DNA hydroxymethylation versus DNA methylation.

    “The authors further showed that repressive MECP2 binding was reduced in areas of DNA hydroxymethylation, likely due to MECP2’s lower affinity for DNA hydroxymethylation versus DNA methylation [ 172 ].”
  • Oxidative damage reduces the binding affinity of MeCP2 to damaged methylated DNA.

    “Studies have shown that oxidative damage reduces the binding affinity of MeCP2 to damaged methylated DNA (Valinluck et al., 2004); therefore, it is possible that oxidative damage that occurs close to an L1 element might release its repression.”

    From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Valinluck et al., 2004

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Authors
Valinluck, V.
Affiliations
Loma Linda University (US)
Corresponding author
Valinluck, V.
Venue
Nucleic Acids Research
Published
2004-08-03
Volume
32
Issue
14
Pages
4100-4108
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
OpenAlex
W2137983089
Cited by
756
References
74
Citations by year
2026: 14 · 2025: 20 · 2024: 18 · 2023: 26 · 2022: 28 · 2021: 30 · 2020: 31 · 2019: 35 · 2018: 38 · 2017: 46 · 2016: 55 · 2015: 47 · 2014: 56 · 2013: 75 · 2012: 72
FWCI
2.84
Type
journal article
Language
en
Open access
Locations
  • Nucleic Acids Research (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Loma Linda University
  • National Institutes of Health
  • National Cancer Institute (R01CA084487, CA84487)
  • National Institute of General Medical Sciences (R01GM050351, GM 50351)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
oxidative DNA damage, MeCP2, methyl-CpG binding domain, DNA methylation, 8-oxoguanine, 5-hydroxymethylcytosine, 5-methylcytosine, protein-DNA interactions, epigenetic inheritance, chromatin organization, gene silencing, cancer epigenetics
MeSH terms
Base Sequence, Binding Sites, Chromosomal Proteins, Non-Histone, Cytosine, DNA Damage, DNA-Binding Proteins, Guanosine, Models, Molecular, Oligodeoxyribonucleotides, Repressor Proteins, Protein Structure, Tertiary, Oxidative Stress, CpG Islands, DNA Methylation, Electrophoretic Mobility Shift Assay, 5-Methylcytosine, Methyl-CpG-Binding Protein 2

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