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

• Published in: Chemical communications (Cambridge, England) Vol. 54; no. 9; pp. 1061 - 1064
• 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: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 2018
• 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
• ISSN: 1359-7345; 1364-548X
• DOI: 10.1039/c7cc06867k

5-Methylcytosine ( C) is an endogenous modification of DNA that plays a crucial role in DNA-protein interactions, chromatin structure, epigenetic regulation, and DNA repair. 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.