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Summary Lecture 7 - Posttranscriptional gene control and nuclear transport #3
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Lecture 7 - Posttranscriptional gene control and nuclear transport #3
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Biochemistry and Molecular Biology II – Lecture 7: Posttranscriptional genecontrol and nuclear transport #3 – Lecture by Ger Pruijn
14-05-2018
Post transcriptional regulation in the cytoplasm:
The efficiency of mRNA translation/survival is regulated by micro and siRNAs.
Regulation can be very cell-specific or mRNA specific.
MicroRNAs (miRNAs) and RNA-interference:
mRNA precursors/double-stranded RNA can be converted into ds miRNA/siRNA by
dicer the ds mi/siRNA associates with RISC-complex (RNA-induced silencing
complex). When associated with RISC, the si/miRNA is active two different routes
are followed:
1. Perfect/complete base pairing: target cleavage (siRNAs)
2. Incomplete base pairing: translation repression (miRNAs)
- siRNAs are usually not encoded in the genome, but introduced by
viruses/researchers, in order to regulate gene expression.
- miRNAs are encoded in the genome.
Nucleotides 2 to 7 of a miRNA are the most critical for targeting it to a specific
mRNA.
Exportin 5 is specialized in transporting pre-mRNA from the nucleus into the
cytoplasm.
, Drosha (in the nucleus) generates one end of the
miRNA, by cleavage
Dicer (in the cytoplasm) is an RNase II
endonuclease that generates the other end of the
miRNA.
TRBP (in the cytoplasm) is a double strand RNA
binding protein (dsRBP) that is required for the
recruitment of Ago2 (Argonaute protein) to the
small interfering RNA (siRNA) bound by Dicer.
TRBP increases HIV-1 expression and replication
by inhibiting the interferon-induced protein kinase
PKR and by increasing translation of viral mRNA.
Dicer, Ago2, and TRBP are the main components
of the RNA-induced silencing complex (RISC)
(source: https://www.phosphosite.org/proteinAction?id=15651&showAllSites=true)
Argonaute protein: one strand is released, other
strand remains bound to the RISC-complex.
Argonaute proteins activate and cleave the mRNA
RNAi
Ago2 is an RNase and is the catalytic center of
RISC catalyzing mRNA
Binding of RISC to a perfectly complementary mRNA
generally results in silencing due to endonucleolytic cleavage of the mRNA specifically by
AGO2. Binding of RISC to a partially complementary mRNA results in silencing through
inhibition of translation, and this is independent of endonuclease activity. (Source:
https://www.uniprot.org/uniprot/Q9UKV8)
The RISC-complex consists out of the loaded ds
mi/siRNA + dicer + TRBP + Ago2 (Argonaut
protein).
*siRNAs are complementary to their target mRNA.
Often, a combination of miRNAs leads to efficient
regulation of RNAi.
- miRNA-regulation is very cell-specific;
miRNAs are not expressed in any cell.
RNA-interference takes place due to interference by siRNAs and miRNAs.
Amplification of RNAi-effects in plants and worms:
A small amount of trigger dsRNA is processed into siRNA;
RdRP (RNA-dependent RNA polymerase) reaction converts target mRNAs into new
dsRNAs.
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