. DNMT1 is an enzyme of vital importance in mammals since it is responsible for the inheritance of methylation patterns by daughter cells after every replication cycle, a process called maintenance methylation. The significance of DNMT1 and maintenance methylation can be displayed by the fact that mice homozygous for deletion of DNMT1, die approximately 9 days after their conception. This occurs because DNMT1 is necessary for their development.
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| Methylation event[ Diagram taken from Cytosine methylation and DNA repair. C.P. Walsh and G.L. Xu. Curr Top Microbiol Immunol., 2006, 301, 283-315 [Review]] |
Methylation is a form of heritable DNA modification and is one of the reasons cells with the same genetic material are able to perform completely different functions. Through methylation, gene expression patterns can be altered and genes can be silenced allowing differentiated cells to retain their function throughout the life of an organism . Methylation is also involved in silencing of foreign genes incorporated in the genome parasite or viral retrotransposons. Furthermore, methylation is responsible for the differential expression of maternal and paternal genes for certain characteristics. This is the phenomenon called genetic imprinting. Genes which are genetically imprinted are differentially methylated during gametogenesis in each parent.The methylation paterns these genes receive are resistant to the demethylation wave that takes place when the blastocyst is formed and to the de-novo methylation that follows. As a result, the offspring receives anormal gene from one parent and an imprinted,inactive gene from the other. These phenomenon is associated with certain diseases such as Prader-Willi syndrome(paternally inherited) and Angelman syndrome(maternally inherited) both caused by deletion of a specific region in chromosome 15. Lastly, methylation and DNMT1 are involved in several forms of cancer, by causing a mutation that can activate proto-oncogenes.
Having covered some backround information, its time for us to examine the mechanisms of methylation and how DNMT1 functions. Focus is going to be given on how structural characteristics of the enzyme contribute to its function.
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| DNMT1 stucture(light blue0 binding a DNA double helix(red/orange) with a Zn atom embeded(green).[addapted from http://www.rcsb.org/pdb/101/motm.do?momID=139] |
