Cell and Molecular Biology of DNA Methyltransferase 1 - International Review of Cell and Molecular Biology - page 26

b -cell regeneration in a model of pancreatic b -cell ablation. These results
suggest that Dnmt1 is dispensable for endocrine cell formation but essential
for acinar cell survival. Therefore, DNMT1 may influence the differentia-
tion of pancreatic b -cell progenitors or the process of differentiation into
pancreatic b cells ( Anderson et al., 2009 ).
Conditional deletion of the Dnmt1 gene in neuroblasts resulted in con-
trasting effects in postmitotic neurons and CNS precursor cells. Loss of
DNMT1 in postmitotic neurons did not affect their survival or DNA meth-
ylation patterns, whereas in CNS precursor cells, in absence of DNMT1,
there was genomic hypomethylation and functional impairment of the cells
( Fan et al., 2001 ). These hypomethylated cells were selected against in post-
natal development. Additional evidence supporting the view that catalytic
activity of DNMT1 is required for survival of differentiating cells comes
form in vitro studies by Damelin and Bestor (2007) . In these experiments,
Dnmt1 c/c cells (null for DNMT1 protein) were transfected with constructs
expressing wild-type (DNMT1 WT ) and catalytically inactive
(DNMT1 C1229S ) proteins. The ability of these proteins to support successful
differentiation and survival was investigated. The authors observed that
while the wild-type protein supported normal differentiation and survival
of differentiated cells, the catalytically inactive protein did not supply these
functions. These results also demonstrate that DNMT1 facilitates proper
location of macroH2A1 to the inactive X chromosome and imprinted loci.
4.6. Roles for Dnmt1 in DNA repair and radiation-induced
DNA damage
First indication that DNMT1 may play a role in DNA repair came from a
genetic screen wherein mutations conferring defects in mismatch repair to
mouse ES cells were identified ( Guo et al., 2004 ). Subsequently, a number of
mouse models in which Dnmt1 or other de novo methyltransferases are
deleted showed instability in some types of the repeats suggesting that loss
of methylation may be responsible for the observed genomic instability.
Cells lacking either Dnmt1 or all of Dnmt1 , Dnmt3a , and Dnmt3b showed
decreased instability of subtelomeric repeats suggesting that even stability
of repeats lacking CpG dinucleotides is dependent on DNMT1 ( Gonzalo
et al., 2006 ). In order to understand the relationship between DNMT1
and genomic instability, Loughery et al. (2011) studied the levels of mis-
match repair proteins in cells wherein Dnmt1 was knocked out. The results
showed that DNMT1 knockdown affects both MutL a and MutS a com-
plexes via downregulation of key components of these complexes. This