RNA Editing by Mammalian ADARs - Advances in Genetics - page 92

Both TRN 1 and Exp-5 bind to an overlapping region of ADAR1 so binding is
mutually exclusive. As export is enhanced by binding to dsRNA and import is
abolished, this gives directionality to export of dsRNA and prevents dsRNA
from being reimported. ADAR1 has been shown to localize to the nucleolus in
some mammalian cell lines (Desterro

, 2003). Photo-
bleaching experiments indicate this localization is dynamic, and the protein
leaves the nucleolus to interact with substrates; therefore, its localization to
the nucleolus may be for storage purposes (Desterro

et al. , 2003; Sansam et al.

et al. , 2003).

1. ADAR1-null mice
Unlike ADAR2, there is no known essential editing event that depends exclu-
sively on ADAR1. ADAR1 does edit specific sites such as three of the five
editing sites in exon 5 of the serotonin 5-hydroxytryptamine subtype 2C (5-
HT 2C ) receptor (Burns

Adar1 /
mice displayed a severe embryonic phenotype of massive liver disintegration and
died at embryonic day (E) 12.5 (Hartner

et al. , 1997). It was therefore surprising when

, 2004)asno
ascribed role for ADARs during development and no edited transcripts has been
found in the liver. Characterization of the

et al. , 2004; Wang et al.

Adar1 / liver phenotype revealed a
defect in proliferation of hematopoietic cells, with those present showing frag-
mented DNA indicative of apoptotic cell death. The heterozygous mice were
indistinguishable from wild type.
Mouse embryonic fibroblast cells derived from

Adar1 / mice dis-
played elevated apoptosis in response to serum starvation indicative of a
widespread predisposition to apoptotic cell death (Jiang et al. , 2004). The

Adar1 / apoptotic phenotype correlated with an induction of
the interferon-inducible ADAR1 p150 isoform following serum starvation
implying a role for ADAR1 in mediating the induction of apoptosis in response
to stress. Interestingly, analysis of the transcript encoding the HT 2C isolated
from E12

onset of the

Adar1 / embryos showed that exon 5, which contains all five editing
sites, was aberrantly spliced out. This implies that splicing and editing at these
sites in the HT 2C transcript are coupled (Hartner

, 2004).
Further characterization of the liver phenotype in mice with induced
disruption of

et al.

in the hematopoietic system revealed that ADAR1 is crucial
for the maintenance of hematopoietic stem cells (Hartner

Adar1

, 2009). Another
group found that ADAR1 was instead required for the survival of hematopoietic
progenitor cells (XuFeng

et al.

, 2009). During liver development, ADAR1
somehow acts to suppress interferon signaling and in the absence of ADAR1
elevated apoptosis occurs with aberrant activation of interferon-inducible genes.
Therefore, the hypothesis has been proposed that some unknown substrate of
ADAR1 is critical

et al.

for correct interferon response during embryonic liver