Biology Reference
In-Depth Information
remains to be elucidated, although one study suggests that piRNAs also
come from repeat elements and may be produced by a mechanism
similar to that in flies.
60
5. Function of Small Regulatory RNAs
Many independent experiments showed that miRNAs can reduce mRNA
translation either by triggering endonucleolytic cleavage of the mRNA or
by promoting repression of translation. In contrast to plants, in which
most known miRNAs hybridize almost perfectly with their targets and
direct endonucleolytic cleavage,
69
most metazoan miRNAs have only par-
tial complementarity to their targets and trigger translational repression
(reviewed by He and Hannon
70
). The binding of miRNA to mRNA may
be facilitated by other RNA-binding proteins such as GW182/
TNRC6,
71-73
which are components of the so-called P bodies,
74
and may
be modulated under specific conditions by RNA-binding proteins such as
HuR
75
and the Dead-end protein.
76
The function of Ago proteins in the
RISC complex appears to be manyfold. The crystal structures of
Argonaute proteins from
Pyrococcus furiosus
77
and
Achaeoglobus fulgidus
78
suggested that the PIWI domain of these proteins, which bear striking
similarity to RNase H, is responsible for Slicer activity, performing the
small RNA-directed endonucleolytic cleavage of mRNA in RISC. X-ray
and nuclear magnetic resonance (NMR) studies of Argonaute PAZ
domains, both free and complexed with RNA, revealed that the domain
specifically recognizes the two-nucleotide 3
overhang of the duplex or
the 3-OH end of a single-stranded RNA.
8,79
Finally, it has been recently
demonstated that the human Ago-2 directly binds the m
7
G cap of
mRNA targets, most likely preventing the recruitment of eIF4E and
blocking initiation of translation.
80
Although translational repression is believed to be the main mecha-
nism of miRNA activity in animals, some amount of miRNA-induced
degradation has been demonstrated.
81,82
In a specific system, namely early
development of zebrafish, miRNA-induced mRNA deadenylation and
degradation are the main mechanisms behind the clearance of maternal
mRNAs.
83,84
To what extent miRNA binding is followed by mRNA
degradation in mammals, and whether translational inhibition and
′
