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 language | English (US) |
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Pages (from-to) | 1061-1064 |
Number of pages | 4 |
Journal | Chemical Communications |
Volume | 54 |
Issue number | 9 |
DOIs | |
State | Published - 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.