This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. RNA interference (RNAi) is a conserved sequence-specific gene regulation process in eukaryotes triggered by double-stranded RNAs (dsRNAs). Human DICER processes these dsRNAs, or alternately endogenous precursor-microRNAs (pre-miRNAs), into small interfering RNAs (siRNAs) or miRNAs, respectively. These RNAs are around 21-nucletides in length, and are characterized by a phosphate at the 5 -end and a 2-nt overhang at the 3 end. The siRNAs and miRNAs are taken up into the RNA-induced silencing complex (RISC), where they mediate guide strand-mediated sequence-specific cleavage or translational repression of mRNAs. Recently, the crystal structure of Giardia DICER in the free state, solved in the Jennifer Doudna laboratory, has defined the relative arrangement of the PAZ and RNaseIII modules and linker elements. The overall architecture is hatchet-shaped, with a fixed distance separating these modules. We are attempting to solve the crystal structure of a PAZ-containing module of human DICER (hdPAZ) bound to a siRNA duplex. The structure of the complex should provides insights into the principles associated with DICER-mediated recognition of dsRNA.
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