Biology Reference
In-Depth Information
processing can be mediated through binding of ADARs to pre-miRNAs thereby
preventing cleavage by Drosha and does not require catalytic activity of ADAR
(Heale
, 2009a). RNA editing of pri-miR-151 resulted in inhibition both of
its cleavage by Dicer and accumulation of edited pre-miR-151 (Kawahara
et al.
,
2007a). Yang and colleagues found that processing of pri-miR-142 by Drosha was
inhibited by editing of adenosine residues located close to the Drosha cleavage
site (Yang
et al.
, 2006). Consequently, downstream Dicer processing was also
inhibited; however, edited pri-miR-142 did not accumulate to high levels due to
specific degradation of inosine-containing pri-miR-142 by Tudor-SN. Therefore,
editing of pri-miR-142 serves to reduce the level of mature miR-142 by targeting
the edited miRNA for degradation. Higher levels of endogenous miR-142 were
found in ADAR-null mice confirming that this mechanism is used
et al.
in vivo
to
regulate miR-142 levels (Yang
, 2006). Therefore, ADARs can reduce the
abundance of a particular miRNA by inhibiting processing either by binding to
or by editing miRNAs. As often different miRNAs can target the same tran-
script, it is not certain that reducing the abundance of one particular miRNA
will affect the overall expression of the target transcript.
As mentioned previously, UTRs are highly edited (Li
et al.
, 2009) and
editing of miRNA complementary seed sequences has been found (Borchert
et al.
et al.
, 2009). This is a more specific way of altering the RNAi response to a
particular transcript as editing the 3
0
UTR is specific for that transcript and there
is no miRNA redundancy problem.
Caenorhabditis elegans
contains two
adar
genes and strains lacking both
adr-1
were used to investigate antagonism between ADAR and RNAi
(Knight and Bass, 2002). The
and
adr-2
mutant worms had strong somatic
transgene-induced RNAi which was absent from wild-type worms. This is due
to editing of the dsRNA in wild-type worms which prevents the dsRNA from
being cleavage by Dicer and entry into the RNAi pathway. However, the RNAi
pathway is different in
adr-1/adr-2
C. elegans
so how it antagonize ADAR may be unique to
nematodes.
XII. ADAR AND DISEASE
A link has been established between decreased levels of ADAR activity and
tumor progression (Cenci
, 2007).
Decreased editing of the GluR-B and serotonin receptor transcripts was observed
in malignant gliomas and a correlation was shown between tumor stage and
editing level indicating a progressive loss of editing (Maas
et al.
, 2008; Maas
et al.
, 2001; Paz
et al.
, 2001). However,
the levels of ADAR proteins remained unchanged suggesting that the change in
activity was due to posttranslational regulation of ADAR.
et al.
