# A Novel RNA Polyphosphatase PIR-1 Plays Important Roles in Silencing Viruses and Regulating Genes in C. elegans

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2020 · $326,550

## Abstract

Project Summary/Abstract
Dysregulation in gene expression is involved in most human diseases including cancers, developmental
defects, and viral infections. Many therapeutic tools target defects in gene expression. The PI will study a key
step in gene regulation – 'how nascent triphosphorylated RNAs (ppp-RNAs) are regulated?'. RNA interference
(RNAi) plays important roles in regulating genes, including viral and 'harmful' genes in all domains of life. This
project will systematically examine how a highly conserved RNA polyphosphatase, C. elegans PIR-1, regulates
gene expression by modifying ppp-RNAs in RNAi and non-RNAi-mediated pathways. In textbooks, nascent
RNAs are synthesized as ppp-RNAs, which, as gene expression intermediates, are immediately converted to
capped RNAs for protein expression or other functions. This study will demonstrate how an RNA
polyphosphatase can change the fate of nascent ppp-RNAs, thereby modifying the textbook model. This gene
regulation mechanism will serve as a new tool to regulate genes in research and therapeutics. Previous
studies have indicated that human PIR-1 (hPIR1), a novel RNA polyphosphatase, removes two phosphates
from ppp-RNAs to generate p-RNAs in vitro, which are then degraded. This activity renders PIR-1 a candidate
for regulating ppp-RNAs including nascent mRNAs and viral RNAs. Consistently, previous studies suggested
hPIR1 may be involved in regulating specific genes critical for cell proliferation in normal and tumor cells;
however, these studies have provided few insights into: 1) what are the targets genes of PIR-1; 2) how PIR-1
works in vivo. The PI has identified two types of RNA substrates for C. elegans PIR-1, viral RNAs and
endogenous mRNAs, both of which are silenced by PIR-1-mediated RNAi pathways. These preliminary results
are consistent with the previous observation that PIR-1 may interact with Dicer, a central component of RNAi.
Although the mechanism of RNAi has been extensively examined, previous studies have provided few insights
into whether the ppp group on viral and cellular double-stranded (ds)RNAs plays any role in RNAi. The PI
proposes PIR-1 may modify ppp-dsRNAs to generate p-dsRNAs, promoting Dicer to efficiently cut dsRNAs in
C. elegans. The PI will systematically dissect the molecular mechanism of how PIR-1 regulates genes in these
RNAi processes. The PI will also examine how PIR-1 regulates nascent ppp-RNAs in non-RNAi processes
which play essential roles in the fertility of C. elegans. C. elegans is a robust genetic system especially in RNAi
fields, and studies using C. elegans have led to several breakthroughs including three Nobel prizes in the last
decade. The proposed research is original and innovative since it examines an underexplored yet key gene
regulation mechanism. This research may lead to the development of more effective tools for regulating viral
and endogenous genes. This project will have a significant and long-lasting impact on broad scientific inquiri...

## Key facts

- **NIH application ID:** 9901586
- **Project number:** 5R01GM124349-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Weifeng Gu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $326,550
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901586

## Citation

> US National Institutes of Health, RePORTER application 9901586, A Novel RNA Polyphosphatase PIR-1 Plays Important Roles in Silencing Viruses and Regulating Genes in C. elegans (5R01GM124349-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9901586. Licensed CC0.

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