and Function of
DNA Methyltransferase 1
Willie Miller-Little & Austin Griffin
important for the epigenetic regulation of genes, through
Maintenance of such methylation, in mammals,
is primarily mediated by DNA methyltransferase1-(DNMT1).
DNMT1 is a 1620 residue protein composed of a CXXC
also contains a Target
structures of both the mouse and the
Human DNMT1 protein have been solved.
These two proteins share 85% sequence identity
and share very
structures. This protein functions by
the CXXC domain binding specifically to hemimethylated CpG
interacts in such a way that the CXXC-BAH1 linker between DNA
and the protein’s active site,
preventing de novo methylation. It also
performs an autoinhibitory mechanism in which unmethylated CpG sites
occluded from the active site, selecting for Hemimethylated CpG
CXXC domain (residues 650-699)
contains a crescent like fold.
single domain makes all sequence specific interactions with the DNA.
interactions target both the major and the minor groove, and contain a
footprint. The Major groove interactions are made between the
form a loop segment
that penetrates the major groove,
contact the Guanine bases
via hydrogen bonds
in the unmethylated dinucleotide
with the cytosine bases.
these are not the only
interactions made with the
DNA, the CXXC
domain also contains recognition sites of salt bridges
phosphodiester backbone of the DNA
. The CXXC
domain also aids
in the control of not interacting with Methylated CpG sites.
occurs due to steric
hindrance. If a methyl group were
present on the CpG
dinucleotide, it would
unfavorably interact with (Arg684
Lys686 ) due to steric
interference with nearby peptide atoms
The BAH1 and
domains adopt a common fold similar to the Orc1p BAH domain.
domains are connected by an alpha helix (BAH linker)
and form a dumbbell like configuration
physically associated with the methyltransferase domain. The BAH1
is anchored to the linker alpha helix by a Cys3His-coordinated
while the BAH2 domain loop is anchored
to the TRD
Methylt transferase domain in DMNT1 is the
main catalytic domain of the protein. It contains two
Target recognition domain (TRD), and the catalytic core, which are
a large cleft in the protein, which is occupied by the DNA.
core is composed of seven mixed β-sheets
flanked on either side by
DNA in mDNMT1 complex is anchored by the
CXXC domain, withdrawn from the DNMT1 active site.
Unmethylated DNA is
occluded from the active site because f the autoinhibitory function of
CXXC-BAH1 linker (highlight and zoom, rotate). The CXXC-BAH1
contains a highly acidic segment spanning residues D703-D711
is positioned between the DNA and the active
The BAH2-TRD loop also
TRD in a retracted position, preventing major groove interactions with
the DNA. These
two activities function to prevent
unmethylated Cpg dinucleotides from entering the active site, and only
hemimethylated dinucleotides to enter the active site.
J.A. Law, S.E.
Jacobsen, Nat. Rev. Genet. 11, 204 (2010).
X. Cheng, R.M. Blumenthal, Structure 16, 341 (2008).
M. G. Goll, T.H. Bestor, Annu.
Rev. Biochem. 74, 481 (2005).
4. Song J. et. al. Structure of DNMT1-DNA Complex Reveals a
Role for Autoinhibition in Maintenance DNA Methylation. Science
vol. 331. (25, February, 2011 )
James D. Molecular
Biology of the Gene 3d Ed.with Ill.by Keith Roberts. 6th
Menlo Park,Calif: W.A.Benjamin, 1976.
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