Fig. 1 miRNA biogenesis and mechanism of function .
Pre-miRNAs are transcribed from the miRNA gene by RNA polymerase enzyme
in the nucleus. They are processed by Drosha (RNase III enzyme) and
Pasha (DGCR8) to give pre-miRNA transcripts of ~70
nucleotides length, which form stem-loop structures. Pre-miRNAs are
exported to the cytoplasm, where they are processed by Dicer (RNase II
enzyme) and then loaded into the mRISC complex containing the Argonaute
(Ago) proteins. miRNA in the mRISC complex is guided by Ago towards the
binding site in the target 3’UTR. After binding to the target mRNA,
target repression occurs via mRNA degradation or translation based on
the complementarity between the mRNA and miRNA seed sequence2,3,49.
miRNAs in the mRISC complex then recognizes the target mRNA and directs
it for decay and/or translation repression along with other RNA binding
proteins (Fig. 1 ).2,3,49 The
m7GTP cap structure in the 5’ end and poly-A tail in
the ‘3’end of mRNA is important to initiate translation in
eukaryotes.50 MicroRNAs are known to inhibit various
stages of the translation process such as initiation, elongation, and
maturation. The eukaryotic initiation factor complex consisting of
eiF4F, eiF4G and eiF4A) recognizes and binds to the cap structure in the
5’end and recruits a small 40s ribosomal unit for translation. During
translation, Poly A binding protein (PABP) recruited by GW182 binds to
the poly-A tail present in the 3’end of mRNA and eiF4G interacts with
PABP to circularize the mRNA.2,50 Binding of RISC
complex with miRNA to the mRNA disrupts the interaction between eiF4F
and PABP, causes decapping and deadenylation of the mRNA, which
eventually leads to mRNA decay.2,51 Modeling these
detailed events is not easy with limited quantitative experimental data.
However, attempts have been made to model other features of miRNA
regulation dealing with factors such as binding site complementarity,
the number of binding sites, the relative abundance of miRNA and mRNA,
presence of competing RNAs and RISC binding proteins, which influence
the efficiency of miRNA mediated target repression
effectively.52–55