# Mechanisms of Microprocessor Function and Regulation

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $332,855

## Abstract

Project Summary/Abstract (30 lines)
MicroRNAs (miRNAs) constitute a large family of short, non-coding, regulatory RNAs. To generate functional
miRNAs, primary transcripts (pri-miRNAs) need to be first cleaved by an RNAse III enzyme, Drosha. This
critical step of miRNA maturation needs to be strictly controlled, and dysregulation is associated with many
diseases. Processing efficiency can also tuned through various means, including post-transcriptional
modification of RNA, such as adenosine methylation by Mettl3/Mettl14 complexes. In addition, Drosha is
dependent on its partner protein, DGCR8. DGCR8 is regulated at the mRNA and protein levels, and is also
regulated by heme binding. However, mechanistic details of how pri-miRNA processing is carried out and
regulated remain largely unknown, leaving many questions unanswered: 1) what makes a pri-miRNA a good
substrate for processing by Drosha? 2) how are processing rates modulated by changes in RNA modification
or conformation? 3) why does Drosha require a cofactor protein (DGCR8), unlike other RNAseIII enzymes?
and 4) how do DGCR8 and Drosha cooperate to recognize, bind and precisely cleave substrate RNAs?
 Our long-term goal is to understand miRNA processing and regulation at the atomic level. The
Drosha/DGCR8 complex (also called Microprocessor) must efficiently process thousands of different
transcripts, with single-nucleotide precision. Our broad hypothesis is that RNA features—sequence and
structure—dictate the processing fate of each individual pri-miRNA. Our proposed study focuses on elucidating
a model for how Microprocessor recognizes and interacts with pri-miRNAs, and identifying the features of pri-
miRNAs that allow specific pathways to regulate processing. Our specific objectives are to: 1) Determine how
N6-methyladenosine (m6A) modification of pri-miRNAs modulates processing efficiency, thereby identifying the
pri-miRNA features that are important for Microprocessor activity; 2) determine how DGCR8 in its heme-bound
state helps Drosha, thereby dissecting the molecular role of DGCR8 in pri-miRNA processing; and 3) Reveal
three-dimensional structures of Microprocessor/pri-miRNA complexes to explain the biochemical observations
in the first two Aims.
 As a class of molecules devoted to gene regulation, miRNAs are involved in every major area of biology,
and Microprocessor is required for proper maturation of almost all miRNAs. Our proposed studies will together
elucidate how Drosha and DGCR8 cooperate to recognize certain features of pri-miRNAs. In addition to
providing a basic physical framework for how Microprocessor works, the molecular mechanisms that we
discover will lay the groundwork for investigating various ways to regulate individual miRNAs, opening doors to
developing new therapeutic agents to target gene regulation.
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## Key facts

- **NIH application ID:** 9895830
- **Project number:** 5R01GM122960-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Yunsun Nam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $332,855
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895830

## Citation

> US National Institutes of Health, RePORTER application 9895830, Mechanisms of Microprocessor Function and Regulation (5R01GM122960-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9895830. Licensed CC0.

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