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

D. Kotandeniya, C. L. Seiler, J. Fernandez, S. S. Pujari, L. Curwick, K. Murphy, S. Wickramaratne, S. Yan, D. Murphy, Yuk Y. Sham, N. Y. Tretyakova

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)1061-1064
Number of pages4
JournalChemical Communications
Volume54
Issue number9
DOIs
StatePublished - 2018

Bibliographical note

Funding Information:
This work was supported by the National Cancer Institute (R01CA095039). J. F. was partially supported by an NIH Chemistry–Biology Interface Training Grant (5 T32 GM 8700-18).

Publisher Copyright:
© 2018 The Royal Society of Chemistry.

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