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From
•>>January 2005
- [late entry]
Phillip D. Zamore answers
a few questions about this month's fast moving front in the
field of Molecular Biology & Genetics.
Field: Molecular Biology & Genetics
Title: Asymmetry in the assembly of the RNAi enzyme complex
Author: Schwarz, DS;Hutvagner, G;Du, T;Xu, ZS;Aronin,
N;Zamore, PD
Journal: CELL, 115: (2) 199-208, OCT 17 2003
Addresses: Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Lazare Res Bldg, 364 Plantat St, Worcester, MA 01605 USA.
Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA.
Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA.
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Why do you think your paper is
highly cited?
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“...our discovery meant that an elaborate
protein-based machinery must be examining the thermodynamics of the
ends of each siRNA, loading one strand into the RNAi enzyme effector
complex and designating the other for destruction.”
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For two reasons: First, it revealed an unexpected step in the
assembly of the RNAi enzyme complex. Second, it provided a method
for improving siRNA efficacy, one that was rooted in the biology
of RNAi.
Does it describe a new discovery or new methodology that's
useful to others?
The paper described our discovery that thermodynamic features
of small interfering RNA (siRNA) duplexes determine which strand
of the siRNA enters the RNAi pathway. To us, our discovery meant
that elaborate protein-based machinery must be examining the
thermodynamics of the ends of each siRNA, loading one strand
into the RNAi enzyme effector complex and designating the other
for destruction. Practically, our work explained why a very
large number of siRNAs work poorly: the wrong strand of the
siRNA duplex enters the RNAi pathway.
Could you summarize the significance of your paper in
layman's terms?
RNA interference, which was discovered just a decade ago,
provides biologists a new method to turn genes off. But many of
the molecules (siRNAs), which are used to direct RNA
interference against individual genes, don't work very well. Our
results helped explain why, and they provided a biological
answer as to how to improve them.
How did you become involved in this research?
We were trying to understand why one siRNA, which we had
studied for several years, seemed to work more potently against
sense target RNAs than antisense target RNAs. What started as a
control experiment rapidly became a paradox. Finally, we had an
"aha!" moment when Dianne Schwarz, the first author on
the paper, showed that one could make
changes in the siRNA sequence that
would predictably change which siRNA strand would enter the RNAi
pathway.
Phillip D. Zamore
Associate Professor
Department of Biochemistry & Molecular Pharmacology
University of Massachusetts Medical School
Worcester, MA, USA
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