Biology Reference
In-Depth Information
dsRNA
miRNA precursor
Drosha
Drosha
(Dicer)
(Dicer)
siRNA
miRNA
Argonaute proteins
Effector Complex
RISC
RISC
DNA/histone methylation
mRNA degradation
translation suppression
Figure 1.1 The biogenesis and functional routes of siRNAs and miRNA. Gene silencing is
mediated by the formation of effector complex RISC in which the Argonaute protein is bound
to siRNA or miRNA; the effector complex then suppresses the expression of target genes.
(the Pasha protein of Drosophila, the subunit that recognises the substrate) into pre-
miRNAs, which are then translocated to the cytoplasm where they are further pro-
cessed by Dicer (Bernstein et al., 2001; Lee et  al., 2003; Denli et  al., 2004; Gregory
et al., 2004). The components of the microprocessor complex are said to mutually reg-
ulate one another, which might be a mode of miRNA biogenesis (Han et  al., 2009a).
The complete processing of miRNAs might be more complex than thought at one time
and might involve steps specific to the maturation of individual miRNAs leading to
much diversity in their function (Winter et al., 2009). Similarly siRNAs are also gener-
ated by Dicer-dependent processing complex of double-stranded RNA precursors.
The small RNAs form complexes with specific proteins to form the RNA silencing
effector complexes, namely siRNA complexes called RISCs (RNA-induced silencing
complexes) and miRNPs with miRNAs (Hammond et  al., 2001; Meister and Tuschl,
2004). The mechanisms by which these small RNA modulate gene expression dif-
fer markedly. SiRNAs seem to be able to suppress gene expression by cleaving and
degrading mRNAs that bear sequence identity with them and in this way inhibit protein
synthesis (Valencia-Sanchez et al., 2006). They may also be able to suppress transcrip-
tion of homologous DNA sequences (Grewal and Elgin, 2007; Zaratiegui et al., 2007).
They can methylate promoters of genes and in this way suppress expression (Huettel
et  al., 2007). They can also influence heterochromatin modification. SiRNAs are
implicated in heterochromatin assembly and associated chromatin condensation and
re-organisation of nuclear domains which make it transcriptionally inaccessible and
inactive (Volpe et  al., 2002; Wassenegger, 2005; Grewal and Elgin, 2007; Zaratiegui
et  al., 2007). MiRNAs are non-protein-coding RNAs highly conserved in evolution
and display a marked ability to negatively regulate gene expression. As stated earlier,
miRNAs are approximately 22-nucleotide long and are double-stranded RNA mol-
ecules (Novina and Sharp, 2004; Meister and Tuschl, 2004). They repress translation
of mRNAs of target genes. A further major difference between siRNAs and miRNA is
that whereas siRNAs are not encoded by specific genes, miRNA are. Also siRNAs may
have a viral origin, but miRNAs are totally endogenous ( Figure 1.1 ).
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