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Ryuya Fukunaga
My first project is on the miRNA biogenesis pathway.
miRNAs are 19-24nt single-strand RNAs, which function to
regulate gene expression by binding to the 3' untranslated
region of target genes with almost complete complementation
and lead to translational inhibition. miRNAs are critical for
cell differentiation and histogenesis. miRNAs are generated
as follows. First, long RNA (pri-miRNA) is transcribed from
DNA. As a result, a hairpin loop is formed in the nucleotide
region of the pri-miRNA. This hairpin loop eventually becomes
its final product, miRNA. The large protein complex called
'Microprocessor' cleaves the outer regions of the stem loop
structure in pri-miRNA and produces pre-miRNA, which is a
precursor of miRNA. Pre-miRNA is exported from the nucleus to
the cytoplasm, is then cleaved by Dicer, and finally becomes
mature miRNA. Components of Microprocessor contain Drosha
(class III RNase, 150 kDa), DGCR8/Pasha (double strand RNA
binding protein, 75 kDa), and other unidentified factors.
By determining the X-ray crystal structures of Microprocessor
and its complex with pri-miRNA, and by doing biochemical work,
I would like to determine how the Microprocessor is organized,
how it selectively recognizes pre-miRNA in a correct orientation
without recognizing other RNAs, and how it catalyzes cleavage
reaction.
My second project is on the P-bodies (processing bodies).
P-bodies are microscopic structures within the eukaryotic
cell, made up of many enzymes involved in mRNA turnover.
P-bodies capture many mRNAs, which become unavailable for
the translational machinery; degrade unwanted mRNAs that
lack a 5' cap; store mRNA until needed for translation; and
aid in translational repression by miRNAs. My goal is to
elucidate the mechanism of these P-body's activities using
X-ray crystallography and biochemistry.
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