How Microprocessor
precisely initiates miRNA production
A scientific group
from the Center for RNA Research
within the Institute for Basic Science
(IBS) and School of Biological
Sciences in Seoul National University has reported an insightful molecular mechanism of how Microprocessor, the
DROSHA-DGCR8 complex, precisely determines cleavage sites on miRNA-containing
primary transcripts allowing faithful initiation of microRNA biogenesis.
The group’s findings, published in Cell on 28th May as Advance
Online Publication, not only reveal the function of each part of human
Microprocessor, but also outline future
work on the molecular structure of the protein complex which will enable various
new applications of RNA interference technology in basic research and human
therapeutics.
MicroRNAs (miRNAs) are short RNA species of ~22
nucleotides, but play critical roles in a wide variety of cellular processes,
including stem cell differentiation and tumorigenesis. Their gene silencing mechanism
is dependent on their sequences which are acquired through the miRNA production
process, called miRNA biogenesis. This process is initiated in the nucleus by Microprocessor,
a complex of the catalytic subunit DROSHA and a co-factor DGCR8, which cleaves primary
transcripts (pri-miRNAs) containing miRNA sequences. It is thought that the pri-miRNA
processing step determines the sequences of miRNAs and thereby their actions,
thus it is greatly important to understand how Microprocessor accurately
process pri-miRNAs.
A group of researchers in IBS and SNU led by Dr. Jae-Sung
Woo and Dr. V. Narry Kim have made a significant advance toward understanding the
molecular mechanism of pri-miRNA processing by using highly pure recombinant
Microprocessor which was lacking in this field. They discovered that Microprocessor
consists of one DROSHA and two DGCR8 molecules.
They also disclosed an important and surprising role of DROSHA as a “molecular
ruler” by showing that DROSHA can recognize the ssRNA-dsRNA junction at the lower
side of pri-miRNA and measure the distance of ~11 base pairs from the junction
to find the precise cleavage sites. DROSHA was also found to specifically recognize
the located at the lower junction,
allowing it to interact with pri-miRNAs more specifically. Over the previous
knowledge, DGCR8 was found to have three functionally distinct parts: the tail
to stabilize DROSHA, the body to enhance the processing efficiency by
recruiting pri-miRNA, and the head to ensure the processing accuracy by
recognizing the upper elements of pri-miRNA including the apical UGU motif.
Dr. Nguyen T. A., the first author of this paper, has integrated
various biochemical, biophysical, and bioinformatical data and proposed a current
model showing that the functional parts of Microprocessor interact with the cis-acting
elements on pri-miRNA for accurate processing. This model also represents an
interesting molecular mechanism of the Microprocessor orientation on pri-miRNAs
which has been unknown so far. Furthermore, it brings out a comprehensive
understanding how Microprocessor acts differently on various pri-miRNA substrates
with different sequence and structural features, and clarify decade-standing
controversies over the pri-miRNA processing mechanism.
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Notes for editors
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References
Nguyen, T. A., Jo, M. H., Choi, Y.-G.,
Park J., Kwon, S. C., Hohng, S., Kim, V. N.* and Woo, J.-S.* (2015) “Functional
anatomy of the human Microprocessor” Cell, in press, (*co-corresponding
authors), DOI: http://dx.doi.org/10.1016/j.cell.2015.05.010
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For
further information or to request media assistance, please contact: Mr. Shi Bo
Shim, Head of Department of Communications, Institute for Basic Science
(+82-42-878-8189; sibo@ibs.re.kr) or Ms. Sunny Kim, Department of
Communications, Institute for Basic Science (+82-42-878-8135; Sunnykim@ibs.re.kr)
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About
Institute for Basic Science (IBS)
The IBS was founded in 2011 by the government of the Republic of Korea. With
the sole purpose of driving forward the development of basic science in Korea,
IBS will be comprised of a total of 50 research centers in all fields of basic
science, including mathematics, physics, chemistry, life science, earth science
and interdisciplinary science. IBS has launched 24 research centers as of
January 2015. There are one mathematics, eight physics, six chemistry, seven
life science, and two interdisciplinary research centers.
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