Biology Reference
In-Depth Information
complementarity to it (for review see Carthew and Sontheimer, 2009). In
summary, siRNAs are cleaved from longer dsRNAs by Dicer in the cytoplasm
and have complete complementarity to their target mRNA. However, miRNAs
are processed from primary miRNAs (pri-miRNAs) that are often encoded
within introns of transcripts. They form stem-loop dsRNA structures that are
cleaved from surrounding the sequence by the microprocessor complex in the
nucleus to generate a pre-miRNA. The pre-miRNA of approximately 75 nt is
then exported from the nucleus and processed further by Dicer to remove the
loop region and produce a mature miRNA (Lee
, 2002). In contrast to
siRNAs, miRNAs can contain mismatches although a critical “seed” region of
4-7 nt must be complementary to their target mRNA. One strand of the mature
miRNA or siRNA associates with the RISC complex (Gregory
et al.
, 2005)to
direct silencing of target mRNAs, which can be mediated through cleavage and
degradation of the transcript or translational inhibition. siRNA and miRNA
activities depend on the formation of dsRNA during their biogenesis and for
functional RNA silencing, and given that ADARs bind dsRNA it has long been
hypothesized that they could modulate the RNAi pathway.
An initial survey to analyze the extent of miRNA editing revealed that
13% of human pri-miRNAs were edited and that levels of editing varied across
the tissues analyzed (Blow
et al.
, 2006). This corresponded to 6% of mature
miRNAs being edited and target site prediction software indicated that editing
of mature miRNA could change their target specificity by redirecting them to
another transcript. A more comprehensive sequence analysis of pri-miRNAs
revealed numerous editing sites and led to the prediction that up to 16% pri-
miRNAs could be edited in human brain (Kawahara
et al.
, 2008), which if
correct would imply that editing of miRNA occurs more frequently than initially
thought. However, only a subset of pri-miRNAs has been found to be edited
indicating ADARs specifically target certain pri-miRNAs and they recognize
more than just dsRNA structure.
The reported consequences of miRNA editing are varied; however, only
one example of redirection of target specificity has been reported. In the case of
the human, miRNA-376 cluster editing occurred to nearly 100% at several sites
(Kawahara
et al.
, 2007b). One editing site was located within the seed region of
the mature miRNA and editing at this site altered the target specificity of the
miRNAs so that it targeted the transcript encoding phosphoribosyl pyrophos-
phate synthetase 1, an enzyme involved in the uric acid synthesis pathway. The
functional consequence of this redirection of the edited miRNA was confirmed
as altered levels of phosphoribosyl pyrophosphate synthetase 1 protein expres-
sion was detected in
et al.
ADAR2
/
.
However, in the cases reported so far editing of miRNA inhibits bio-
genesis of the miRNA by preventing cleavage by either Drosha or Dicer (Heale
et al.
, 2009a; Kawahara
et al.
, 2007b; Yang
et al.
, 2006). This inhibition of
