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The latter possibility is most intriguing, because it would account for the role
of genomic chromatin features in mediating maintenance methylation.
Poly-ADP ribose polymers were shown to bind DNMT1 and inhibit its
enzymatic activity suggesting a role for poly-ADP ribose polymerase 1
(Parp1) in DNMT1 regulation ( Reale et al., 2005 ). In its polyribosylated form,
Parp1 has been shown to bind the promoter of DNMT1 and augment DNMT1
expression. CTCF was shown to be involved in poly-ADP-ribosylation and
activation of Parp1. CTCF is also found as a ternary complex with Parp1 and
DNMT1 to inhibit DNMT1 activity ( Zampieri et al., 2012 ). Parp1 was found
to be essential for demethylation of the genome in primordial germ cells by
activation of Tet1 hydroxylase 1 that may directly or indirectly promote
demethylationof thegenome ( Ciccaroneet al., 2012 ).Downregulationof Parp1
resulted in impairment of genome-wide and locus-specificmethylation.Collec-
tively, these results suggest intricateways bywhichDNMT1 activity andexpres-
sion are regulated by CTCF, Parp1, and modulation of Tet1 hydroxylase 1.
3.5. Intrinsically disordered region of DNMT1
and possible functions
Unstructured or intrinsically disordered domains are common features of
eukaryotic proteins ( Dyson, 2011 ). Although most of DNMT1 is structured,
with crystallographic information available in both the presence and absence
of DNA, there is a large
300-amino acid disordered domain near the amino
terminus ( Borowczyk et al., 2009 ). The primary sequence of this domain con-
tains many features characteristic of other intrinsically disordered proteins,
such as abundance of proline and glycines, stretches of basic and acidic amino
acids, and of course, inability to establish a definitive 3D structure ( Uversky,
2011 ). The DNMT1 proteins of all vertebrate species whose genomes have
been sequenced have large disordered domains that exhibit some degree of
sequence conservation. Interestingly, the size of this disordered domain
increased during vertebrate evolution, with the largest domains found in
eutherian mammals. The possible function of the mammalian DNMT1 dis-
ordered domain will be discussed further in Section 5 .
3.6. Roles of posttranslational modifications to DNMT1
Discrete posttranslational modifications of DNMT1 are important for the
control of DNMT1 levels and hence control of activity during the cell cycle.
A number of amino acid phosphorylations have been shown to be impor-
tant, particularly phosphorylation at serine 146, serine 515, serine 127, and
serine 143 ( Fig. 1.5 ). Casein kinase d / e primarily phosphorylates DNMT1 at
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