THESIS
2020
xv, 115 pages : illustrations (chiefly color) ; 30 cm
Abstract
microRNA (miRNA) synthesis is initiated by the cleavage event of the human
Microprocessor complex on primary microRNA transcripts (pri-miRNAs).
Microprocessor is constituted by DROSHA, which is an RNase III enzyme, and its
obligate RNA-binding partner DGCR8. DROSHA harbors two RNase III domains,
RIIIDa and RIIIDb, which concertedly execute the cleavage on the 3p- and 5p-strands
of pri-miRNAs, respectively. In our study, we demonstrate that the internal loop located
in the lower stem of multiple pri-miRNAs selectively restrains the cleavage of
Microprocessor on their 3p-strand, thereby, stimulating the single cleavage on their 5p-strand.
This single cut product fails to generate miRNA and thereby downregulates
miRNA expression. We can manipulate the ratio of single-c...[
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microRNA (miRNA) synthesis is initiated by the cleavage event of the human
Microprocessor complex on primary microRNA transcripts (pri-miRNAs).
Microprocessor is constituted by DROSHA, which is an RNase III enzyme, and its
obligate RNA-binding partner DGCR8. DROSHA harbors two RNase III domains,
RIIIDa and RIIIDb, which concertedly execute the cleavage on the 3p- and 5p-strands
of pri-miRNAs, respectively. In our study, we demonstrate that the internal loop located
in the lower stem of multiple pri-miRNAs selectively restrains the cleavage of
Microprocessor on their 3p-strand, thereby, stimulating the single cleavage on their 5p-strand.
This single cut product fails to generate miRNA and thereby downregulates
miRNA expression. We can manipulate the ratio of single-cleavage to double-cleavage
products from Microprocessor catalysis on multiple pri-miRNAs by engineering the size
of the internal loop in their lower stem. We successfully alter miRNA production in the
in vitro pri-miRNA processing assays and in human cells. Therefore, the oscillating
level of the single cleavage implies another layer of regulating miRNA expression and
offers an alternative approach to knockdown miRNA level without interfering the
mature miRNA sequences.
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