Can 5-methylcytosine analogues with extended alkyl side chains guide DNA methylation?

5-Methylcytosine ( Me C) is an endogenous modification of DNA that plays a crucial role in DNA-protein interactions, chromatin structure, epigenetic regulation, and DNA repair. Me C is produced via enzymatic methylation of the C-5 position of cytosine by DNA-methyltransferases (DNMT) which use S -ad...

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Bibliographic Details
Published in:Chemical communications (Cambridge, England) England), 2018-01, Vol.54 (9), p.161-164
Main Authors: Kotandeniya, D, Seiler, C. L, Fernandez, J, Pujari, S. S, Curwick, L, Murphy, K, Wickramaratne, S, Yan, S, Murphy, D, Sham, Yuk Y, Tretyakova, N. Y
Format: Article
Language:English
Subjects:
5-Methylcytosine - analogs & derivatives
5-Methylcytosine - chemistry
Chains
Crystallography, X-Ray
Deoxyribonucleic acid
DNA
DNA (Cytosine-5-)-Methyltransferase 1 - metabolism
DNA - chemistry
DNA - metabolism
DNA Methylation
Gene expression
Humans
Models, Molecular
Molecular Structure
Proteins
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Summary:5-Methylcytosine ( Me C) is an endogenous modification of DNA that plays a crucial role in DNA-protein interactions, chromatin structure, epigenetic regulation, and DNA repair. Me C is produced via enzymatic methylation of the C-5 position of cytosine by DNA-methyltransferases (DNMT) which use S -adenosylmethionine (SAM) as a cofactor. Hemimethylated CG dinucleotides generated as a result of DNA replication are specifically recognized and methylated by maintenance DNA methyltransferase 1 (DNMT1). The accuracy of DNMT1-mediated methylation is essential for preserving tissue-specific DNA methylation and thus gene expression patterns. In the present study, we synthesized DNA duplexes containing MeC analogues with modified C-5 side chains and examined their ability to guide cytosine methylation by the human DNMT1 protein. We found that the ability of 5-alkylcytosines to direct cytosine methylation decreased with increased alkyl chain length and rigidity (methyl > ethyl > propyl ∼ vinyl). Molecular modeling studies indicated that this loss of activity may be caused by the distorted geometry of the DNA-protein complex in the presence of unnatural alkylcytosines. The ability of extended forms of 5-methylcytosine to direct DNA methylation by maintenance DNA methyltransferase was investigated.
ISSN:1359-7345
1364-548X
DOI:10.1039/c7cc06867k