# Mechanistic insights into Dicer, a double-stranded RNA processing enzyme

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $366,000

## Abstract

Project Summary/Abstract
 Dicer is an essential enzyme in all animals, where it cleaves double-stranded RNA (dsRNA) precursors
to generate microRNAs (miRNAs) and small interfering RNAs (siRNAs). These small RNAs bind to
messenger RNAs to regulate their expression. The proposed studies are focused on Dicer's helicase
domain, which is most similar to a family of helicases involved in the innate immune response to viral
infection. RIG-I, the founding member of this family, and Dicer, both recognize dsRNA termini. The goal of
the proposed research is to understand how Dicer's helicase domain coordinates recognition of its dsRNA
substrates, their termini and base-paired structures, to promote conformational changes that correlate with
suboptimal (distributive) or optimal (processive) cleavage.
 Established biochemical assays will be used to perform a comprehensive analysis of Dicer's intrinsic
substrate preferences. Features suggested by natural siRNA precursors, such as 5' and 3' overhangs of
various lengths, and disruptions to base-pairing such as mismatches and loops, will be monitored for their
ability to promote Dicer activities (binding, cleavage, and ATP hydrolysis), and to categorize substrates as
optimal or suboptimal. dsRNA substrates that cannot be cleaved by Dicer alone will be assayed in the
presence of dsRNA binding proteins (dsRBPs) that facilitate Dicer cleavage. Experiments to reveal the
mechanism by which dsRBPs allow termini-independent cleavage will be conducted.
 The ability to define conditions that lead to distinct conformational states sets the stage for proposed
cryo-electron microscopy and x-ray crystallography experiments. These are designed to obtain high-
resolution information about the specific substrate interactions involved in the suboptimal and optimal
conformations. Studies are designed to fill gaps in knowledge about how Dicer recognizes its naturally
occurring substrates, both endogenous dsRNA and exogenous viral dsRNA. The proposed research will
create new paradigms for researchers studying Dicer, and those seeking to manipulate Dicer activities for
research or therapeutic uses.

## Key facts

- **NIH application ID:** 9858171
- **Project number:** 5R01GM121706-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Brenda L. Bass
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2017-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858171

## Citation

> US National Institutes of Health, RePORTER application 9858171, Mechanistic insights into Dicer, a double-stranded RNA processing enzyme (5R01GM121706-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9858171. Licensed CC0.

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