MicroRNAs
(miRNAs)—tiny strands of non-protein-coding RNAs—start off as long
strands of precursor miRNAs. These long strands get chopped up by a
special kind of machinery, the “Microprocessor” complex, to transform
them into their shorter functional form. The resulting miRNAs bind to
messenger RNA (mRNAs) molecules, inhibiting their protein production
capacity and thus regulating the levels of hundreds of different
proteins.
But
the Microprocessor complex can also cut up other forms of RNA, such as
mRNAs, which sometimes generate a transient structure that resembles the
target site of miRNAs. Cleaving the wrong RNAs could prove disastrous
for the organism.
In
a paper recently published in Nature Structural and Molecular Biology,
Dr. Eran Hornstein, Prof. Naama Barkai and former Ph.D. students Drs.
Omer Barad and Mati Mann of the Molecular Genetics Department focus on
understanding how the Microprocessor machinery balances the interplay
between efficiency and specificity in the production of miRNAs. “On the
one hand, it should not be overly efficient, as this may come at the
cost of also cleaving unwanted nonspecific RNA substrates. On the other
hand, it should not be too ‘picky’ because exaggerated specificity comes
with the risk of not sufficiently processing genuine miRNAs,” says
Hornstein.
In
an interdisciplinary project, the scientists used mathematical modeling
to characterize the Microprocessor system and then tested their
theories in cells. They predicted that the balance between efficiency
and specificity would be maintained via a feedback loop in which the
Microprocessor detects the amount of precursor miRNA available in the
cell and alters its own production accordingly.
Checking
this premise in mouse and human tissue, the researchers were able to
show that the Microprocessor is indeed attuned to levels of precursor
miRNA, upping its own production if the cell is inundated with precursor
miRNA, or halting production in response to a decrease in the flow of
precursors. This is achieved by the digestion of Dgcr8 mRNA, which
structurally mimics miRNA. By keeping levels in line with precursor
miRNAs, the Microprocessor thus reduces its chances of chopping
off-target RNAs.
Since
small RNAs are produced synthetically as possible new therapies for a
number of diseases, this research may direct efforts to efficiently
produce such therapies in the future. In addition, many other biological
systems need to balance efficiency with specificity, and the team’s
findings suggest that many may do so in a similar way.
Efficiency and specificity in microRNA biogenesis
Source: Weizmann Institute
