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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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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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 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [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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Kallin, E. M., Rodríguez-Ubreva, J., Christensen, J., Cimmino, L., Aifantis, I., Helin, K., Ballestar, E., & Graf, T. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.08.007 · Cited by 92 · see citing works
Chouliaras, L., L.A. van den Hove, D., Kenis, G., Keitel, S., R. Hof, P., van Os, J., W.M. Steinbusch, H., Schmitz, C., & P.F. Rutten, B. (2012) · Current Alzheimer Research · doi:10.2174/156720512800618035 · Cited by 91 · see citing works
Iron and genome stability: an update
Prá, D., Franke, S. I. R., Henriques, J. A. P., & Fenech, M. (2012) · Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis · doi:10.1016/j.mrfmmm.2012.02.001 · Cited by 91 · see citing works
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“…marks in succeeding DNA-replication cycles (Pastor et al., 2011; Valinluck et al., 2004); (iii) 5-hmC blocks the binding of MBPs, in particular MeCP2 or MBD3, which usually confer transcriptional silencing (Ko et al., 2010; Pastor et al., 2011; Valinluck et al., 2004; Yildirim et al., 2011).”
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Prevention of age-related changes in hippocampal levels of 5-methylcytidine by caloric restriction
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Wang, P., You, D., Saravia, J., Shen, H., & Cormier, S. A. (2013) · Particle and Fibre Toxicology · doi:10.1186/1743-8977-10-29 · Cited by 58 · see citing works
Superoxide dismutase 1 knockdown induces oxidative stress and DNA methylation loss in the prostate
Bhusari, S. S., Dobosy, J. R., Fu, V., Almassi, N., Oberley, T., & Jarrard, D. F. (2010) · Epigenetics · doi:10.4161/epi.5.5.11853 · Cited by 50 · see citing works
- Authors
- Valinluck, V.
- Affiliations
- Loma Linda University (US)
- Corresponding author
- Valinluck, V.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-08-03
- Volume
- 32
- Issue
- 14
- Pages
- 4100-4108
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC514367
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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