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PMID: 15302911 Published · epublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Nucleic acids research ·Vol. 32 ·No. 14 ·2004-00-00 ·Pages 4100-8

Valinluck V, Tsai HH, Rogstad DK, Burdzy A, Bird A, Sowers LC

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.

MeSH Terms
5-Methylcytosine/chemistry Base Sequence Binding Sites Chromosomal Proteins, Non-Histone CpG Islands Cytosine/analogs & derivatives,chemistry DNA Damage DNA Methylation DNA-Binding Proteins/chemistry,metabolism Electrophoretic Mobility Shift Assay Guanosine/analogs & derivatives,chemistry Methyl-CpG-Binding Protein 2 Models, Molecular Oligodeoxyribonucleotides/chemistry,metabolism Oxidative Stress Protein Structure, Tertiary Repressor Proteins
Chemicals
Chromosomal Proteins, Non-Histone DNA-Binding Proteins Methyl-CpG-Binding Protein 2 Oligodeoxyribonucleotides Repressor Proteins 5-hydroxymethylcytosine Guanosine 8-hydroxyguanosine 5-Methylcytosine Cytosine
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Valinluck Victoria
Department of Biochemistry and Microbiology, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.
Tsai Hsin-Hao
Rogstad Daniel K
Burdzy Artur
Bird Adrian
Sowers Lawrence C
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Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
1362-4962
DOI
10.1093/nar/gkh739
Published
2004-00-00
Epub
2004-00-09
Pages
4100-8
Language
English
Region
England
NLM ID
0411011
PMCID
PMC514367
Subset
IM
Grants
NCI NIH HHS · R01 CA084487 · United States
NIGMS NIH HHS · R01 GM050351 · United States
NCI NIH HHS · CA84487 · United States
NIGMS NIH HHS · GM50351 · United States
External Links
PubMed source DOI: 10.1093/nar/gkh739 PMC Full Text View journal details
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