DNA methylation is the addition of a methyl group to the DNA base. Genomic methylation is maintained through cell division. Methylation usually occurs at CpG dinucleotide site, however non-CpG methylation is also found as a small percentage of methylation in embryonic stem cells.
structure of un-methylated cytosine and methylated cytosine
Maintenance of DNA methylation is very important in mammals. According to Melanie Enrlich et al., the percentage of cytosine methylation in different cell types varies from 57% to 85% and the maintenance of genomic methylation plays an important role in many processes. For example, genomic imprinting, which is the process of certain genes are expressed in parent-of-origin-specific manner is largely influenced by DNA methylation since the genomic methylation is inheritable from parents. Imprinted gene such as insulin-like growth factor 2 gene (Igf2) and Igf2 receptor gene are differentially methylated and expressed depending on the parental origin. In addition, methylation is required for transcriptional silencing of retrotransposons. Loss of methylation in early germ cells can cause meiotic failure. Also, DNA methylation is required for X chromosome inactivation in females. Since DNA methylation is associated with many important processes including gene inactivation, methylation disorder may lead to diseases such as cancer, Prader-Willi syndrome and Angelman syndrome.
DNA methylation is catalyzed by DNA methyltransferase. There are two types of methyltransferase. One type carries out de novo methylation and binds to un-methylated DNA, which is primarily involved in early development such as DNMT3a and DNMT3b.
Another type of methyltransferase is the maintenance methyltransferase, which catalyzes methylation of hemi-methylated DNA such as DNMT1. DNMT1 catalyzes the transfer of methyl group from S-adenosyl-L-methionine (AdoMet) to hemi-methylated CpG dinucleotides. DNMT1 consists of a foci-targeting domain (RFD), a DNA-binding CXXC domain, 2 bromo-adjacent homology domains (BAH) and a catalytic domain at the C-terminal. This paper uses high-resolution structure of mDNMT1-DNA complex and reveals its auto-inhibition role in de novo methylation.
sequence of mDNMT1
An overview of mDNMT1-DNA complex. pale yellow: DNA, red: CXXC domain, blue: auto-inhibitory linker, yellow: BAH1 domain, megentas: BAH2, green: methyltransferase domain
