Cell and Molecular Biology of DNA Methyltransferase 1 - International Review of Cell and Molecular Biology - page 2

6. De Novo Methylation 33

6.1 Lessons from plants — Biochemical and genetic studies 33

6.2 De novo methylation mechanisms in animals 34

7. Concluding Remarks 34

References 35

Abstract
The DNA cytosine methyltransferase 1 (DNMT1) is a ubiquitous nuclear enzyme that
catalyzes the well-established reaction of placing methyl groups on the unmethylated
cytosines in methyl-CpG:CpG base pairs in the hemimethylated DNA formed by meth-
ylated parent and unmethylated daughter strands. This activity regenerates fully meth-
ylated methyl-CpG:methyl-CpG pairs. Despite the straightforward nature of its catalytic
activity, detailed biochemical, genetic, and developmental studies revealed intricate
details of the central regulatory role of DNMT1 in governing the epigenetic makeup
of the nuclear genome. DNMT1 mediates demethylation and also participates in seem-
ingly wide cellular functions unrelated to maintenance DNA methylation. This review
brings together mechanistic details of maintenance methylation by DNMT1, its regula-
tion at transcriptional and posttranscriptional levels, and the seemingly unexpected
functions of DNMT1 in the context of DNA methylation which is central to epigenetic
changes that occur during development and the process of cell differentiation.

1. INTRODUCTION

Covalent modifications of deoxyribonucleotides in eukaryotes are
mainly confined to cytosines and more remarkably to the 5 position in the
pyrimidine ring of cytosine in defined sequence environments. There are
two types of cytosine methylation in higher eukaryotes and collectively these
are used for the fundamental purposes of epigenetic inheritance and the control
of gene expression. Symmetricmethylation inwhich neighboring cytosines on
oppositeDNA strands are simultaneouslymethylatedoccurs only in5 0 -CpG-3 0
dinucleotides of both animals ( Sinsheimer, 1955 ) and plants ( Gruenbaum et al.,
1981 ), and in the 5 0 -CpHpG-3 0 trinucleotide (H

A, T, or C) exclusively in
plants ( McClelland, 1983 ). In addition, plants also contain CHHmethylation,
referred to as asymmetric cytosine methylation ( Henderson and Jacobsen,
2007 ). Other forms of asymmetric methylation have been observed in some
invertebrate animal species ( Glastad et al., 2011 ). Collectively, studies of
DNAmethylation in animals and plants indicate that there are many sequence
environments in which methylated cytosine bases are found.
Given the diversity of sequence environments inwhich 5-methyl-cytosine
can reside, it is remarkable that cytosinemethylation inmany lower vertebrates

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