Back to the Index...DNA Meth Word document: MethylTrans11.doc
July 2011 Molecule of the Month by David Goodsell 2QRV 3PT6 1MHT

DNA Methyltransferases DNMT1, DNMT3, restriction modification system Hha1
doi: 10.2210/rcsb_pdb/mom_2011_7 (ePub Version  )

Keywords: epigenetics, DNA methylation, DNMT1, DNMT3, restriction modification system Hha1

 

2QRV
DNA methylase DNMT3 PDB 2QRV
DNMT3 adds methyl groups to Cytosine bases in DNA during development of an organism. These methyl groups are important for controlling genes in different types of cells.

3PT6
DNA methylase DNMT1 PDB 3PT6
DNMT1 adds methyl groups to Cytosine bases in newly replicated DNA. These methyl groups are important for controlling genes in different types of cells.

 

 

1MHT
DNA methylase Hha1 PDB 1MHT
Hha1 adds methyl groups to DNA in bacterial cells, as part of the restriction/modification system that protects the cell from viruses.

Introduction Your body is built of skin cells, nerve cells, bone cells, and many other different types of cells.

These cells are different shapes and sizes, and each type of cell builds a characteristic collection of proteins that are needed for its function. However, every cell in your body contains the same genetic information, encoded in strands of DNA. How does each cell decide which genes to use and which ones to ignore?
Genetics and Epigenetics Scientists have discovered that the information in DNA does not end at the simple genetic sequence of bases. Cells layer additional forms of control on top of the genetic code, creating "epigenetic" information that modifies the use of particular genes. In some cases, this control is performed by the positioning of nucleosomes. In other cases, bases in the DNA are methylated, modifying how they are read during protein synthesis.
Clean Slate In the first minutes of life, when we are composed of a single cell, this epigenetic information has been wiped clean. In the fertilized egg, the methyl groups have been removed and every gene is like all the others. Then, as cells divide in the embryo, they have to make choices about what they are going to do-becoming skin cells or nerve cells or their particular fate. At this point, DNA methyltransferases come into play, and they add methyl groups to genes, shutting off some and activating others. The DNA methyltransferase DNMT3, shown here from PDB entry 2QRV, performs this important job, creating the proper epigenetic coding of methyl groups throughout the genome.

Methyl Maintenance Once each cell has decided its fate, this epigenetic code must be maintained for the rest of the life of the organism. When a cell divides, the information must be transmitted to each of the new cells. The DNA methyltransferase DNMT1, shown here from PDB entry 3PT6, performs this job. As DNA is being replicated, it adds the proper methyl groups to the new DNA strands.

The information is propagated in a tricky way. Methyl groups are almost always added to Cytosine bases with the sequence:
---CG---
---GC---

Notice that both strands have a Cytosine, so in a methylated region of DNA, both strands will have a methyl group. When the DNA is replicated, each of the new DNA double helices will have one old strand, complete with methyl groups, and one new strand, which is not methylated. So, DNMT1 just needs to look for CG base steps where only one strand has a methyl group.
DNMT
Restrictive Bacteria Bacteria also use DNA methylation, but they use it to protect themselves from viruses. They build restriction enzymes that cut DNA at specific sequences. Then, they build specific DNA methyltransferases, such as the one shown here from PDB entry 1MHT, that add methyl groups to these sequences. The methyl groups block the restriction enzyme, but still allow proper reading of the bases during transcription and replication. So, the restriction enzyme floats around the cell with nothing to do, until a virus infects the cell. The DNA from the virus typically does not contain any methyl groups, so the restriction enzyme quickly chops it into pieces.
1MHT

click on the image for an interactive Jmol              3PT6                                                          1MHT
PDB

Exploring the Structure Several structures have helped to explain how DNA methyltransferases perform their jobs. PDB entry 3pt6 includes DMNT1 and a small piece of DNA. The enzyme wraps around the DNA and probes the edges of the bases in the DNA. This structure was solved using DNA with no methyl groups, which would normally not be a substrate of the enzyme. Sure enough, the structure shows that the enzyme recognizes the unmethylated bases on both sides, and holds the DNA away from the active site. There is currently no structure of DNMT1 with a
half-methylated DNA, but we can get an idea of how it might act by looking at a bacterial methyltransferase, pdb entry 1mht. The DNA binds deeper in the active site, and flips out the Cytosine base that will be methylated. To take a closer look at these structures, click on the images for an interactive Jmol.

Topics for further exploration The methyl group is provided by the cofactor S-adenosylmethionine during the methylation reaction. Many of the DNA methyltransferase structures were solved with the similar cofactor
S-adenosyl homocysteine in the active site, but PDB entry 3av6 is DNMT1 with SAM bound. Can you find other enzymes in the PDB that use this cofactor? Are they performing similar reactions?
You can use the structure comparison tool to overlap structures of DNMT enzymes and bacterial methyltransferases. Notice that the cores of the enzymes are similar, but the DNMT enzymes are larger. Why do you think our DNA methyltransferases need additional protein domains along with the domain that performs the reaction?
3PT6PT6
References
R. Z. Jurkowska, T. P. Jurkowski and A. Jeltsch (2011) Structure and Function of Mammalian
DNA Methyltransferases. ChemBioChem 12, 206-222. X. Cheng and R. M. Blumenthal (2008) Mammalian DNA Methyltransferases: A Structural Perspective. Structure 16, 341-350.