Cell and Molecular Biology of DNA Methyltransferase 1 - International Review of Cell and Molecular Biology - page 13

putative functions of this region will be discussed in the following few sec-
tions, particularly as they pertain to the maintenance methyltransferase func-
tion of DNMT1.
3.2.2 Preferences for hemimethylated DNA
Despite the large extent of amino acid sequence differences among known
maintenance methyltransferases, it is important to recognize that the role of
their catalytic activity is to maintain DNA fully methylated at symmetric
cytosines, CpG in the case of MET and DNMT, and CpHpG in the case
of CMT3. As discussed above, the evidence for the catalytic role of DNMT1
in maintenance methylation is strong. Direct evidence for a maintenance
methylation role of CMT3 and MET1 is less convincing, but nonetheless
supportive of such an enzymatic function. The main support comes from
genetic studies in Arabidopsis , the results of which indicate that mutant plants
with significant reductions in MET1 or CMT3 protein survive, yet have
significant reduction in cytosine methylation in the appropriate di- or
trinucleotide sequence context ( Bartee et al., 2001; Finnegan et al., 1996;
Ronemus et al., 1996 ).
3.3. Structured, highly conserved regions of DNMT1
and possible functions
Three-dimensional structures of many regions of the human DNMT1 pro-
tein, including regions also present in A. thaliana maintenance met-
hyltransferases, have been mainly determined from X-ray diffraction
analysis of DNMT1 crystals. Many of these structures have been highly
informative regarding the likely roles of these regions in maintenance meth-
ylation. A detailed schematic of the known regions of the human DNMT1
enzyme, including many regions also present in other cytosine maintenance
methyltransferases, is shown at the top of Fig. 1.5 . At the bottom of Fig. 1.5
are shown the approximate positions of the multitude of known interactions
between other proteins and all mammalian DNMT1 enzymes.
Human DNMT1 contains an autoinhibitory function in which the
RFTS domain, CXXC domain (same as CR or cysteine-rich domain),
linker between the CXXC and BAH1 domains, and the loop projecting
from the BAH2 domain together play a role ( Song et al., 2011 ). The CXXC
domain of DNMT1 interacts with DNA in the absence of hemimethylation
and positions the linker (between CXXC and BAH1 domains) in the
catalytic pocket that prevents interaction of unmethylated DNA with
the catalytic domain of DNMT1. This process also involves insertion of