# Understanding double-stranded RNA recognition in human cells

> **NIH NIH R35** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $418,750

## Abstract

PROJECT SUMMARY
Specific recognition of double-stranded RNA (dsRNA) structures underlies key biological
processes from development to antiviral immune responses, and involves a host of dsRNA-
binding proteins. Biochemical and structural studies have delineated how these proteins interact
with model ligands, yet dsRNAs that they encounter in cells are far more complex. Moreover, little
is known about how cells regulate dsRNA recognition. The goal of my lab is to understand how
dsRNA-binding proteins interact with natural dsRNAs in cells, connecting biochemical models of
dsRNA recognition to cellular dsRNA recognition and regulation. In the next five years, we will
focus on dsRNA recognition in microRNA (miRNA) biogenesis and innate immune sensing.
During miRNA biogenesis, Microprocessor recognizes and cleaves hairpin-like structures from
long transcripts called primary miRNAs (pri-miRNAs). My previous research built a unifying model
of human pri-miRNA and discovered that an optimal miRNA hairpin enhances the cleavage of a
suboptimal miRNA hairpin on the same transcript—known as cluster assistance. Because nearly
40% of human miRNAs reside in clusters, with many implicated in diseases and influenced by
cluster assistance, we propose to dissect this fundamental regulatory mechanism in miRNA
biogenesis using biochemical, single-molecule, and structural approaches. Recognition of dsRNA
by innate immune sensors such as RIG-I and MDA5 initiates antiviral responses. Recent studies
show that endogenous dsRNAs can also activate these sensors, sometimes resulting in
autoinflammatory and autoimmune diseases. The recognition of self dsRNAs therefore needs to
be restricted by proteins that modify, degrade or shield endogenous dsRNAs. Building on our
expertise in dsRNA recognition and processing, we will 1) develop new biochemical methods to
identify dsRNA ligands of innate immune sensors, and 2) develop new genetic screen methods
to identify factors that restrict self dsRNA sensing in innate immunity. Together these studies will
provide crucial insights into how cellular dsRNAs are sensed and regulated, with therapeutic
implications for cancer, autoimmune and infectious diseases.

## Key facts

- **NIH application ID:** 10899775
- **Project number:** 5R35GM150953-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Wenwen Fang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2023-08-04 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899775

## Citation

> US National Institutes of Health, RePORTER application 10899775, Understanding double-stranded RNA recognition in human cells (5R35GM150953-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10899775. Licensed CC0.

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