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Cameron Noland
Short double-stranded RNAs (dsRNAs) are capable of regulating
gene expression post-transcriptionally in an evolutionarily
conserved process known as RNA interference (RNAi). A large
protein complex called the RNA-induced silencing complex (RISC)
is integral to this form of gene regulation. Human RISC is
comprised of the RNase III protein Dicer, the dsRNA binding
protein (dsRBP) TRBP, and the PIWI domain-containing protein
Ago2, along with a short dsRNA that is unwound prior to targeting
of a complementary mRNA for repression. Recently, another
dsRBP, PACT, has been found to bind Dicer, Ago2, and TRBP.
The functional significance of this interaction is currently
unknown. Additionally, the overall conformational rearrangements
involved in dsRNA handling by the RISC remain to be elucidated.
The aim of my project is to examine the functional
architecture and molecular dynamics of the human RISC
through the complimentary use of X-ray crystallography and
single-particle reconstruction. In addition, biochemical
approaches will be used to decipher the precise roles that
TRBP and PACT play in the context of the human RISC and its
handling of dsRNA. This combination of approaches may yield
a view of a conformationally dynamic RISC that sheds further
light on the molecular mechanisms of RNAi in humans.
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