# Inositol pyrophosphate dynamics affect RNA 3'-processing/transcription termination

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $339,000

## Abstract

Project summary
Inositol pyrophosphates (IPPs) are signaling molecules involved in diverse cellular processes
from telomere maintenance and apoptosis to vesicular trafficking and cell migration. Alterations
in IPP levels (via mutations in IPP metabolizing enzymes) are linked to human pathology including
cancer, obesity, diabetes and hearing loss. The pleiotropic effects suggest that inositol
pyrophosphates have the ability to control very basic cellular functions. IPPs are known to
participate in phosphate sensing and phosphate homeostasis in yeast, plant and mammalian
cells. Fungi respond to phosphate starvation by inducing the transcription of phosphate
acquisition genes. The phosphate regulon in the fission yeast Schizosaccharomyces pombe
comprises three genes that specify, respectively, a cell surface acid phosphatase Pho1, an
inorganic phosphate transporter Pho84, and a glycerophosphate transporter Tgp1. Expression of
pho1, pho84, and tgp1 is actively repressed during growth in phosphate-rich medium by the
transcription in cis of a long noncoding (lnc) RNA from the respective 5' flanking genes prt, prt2,
and nc-tgp1. It is proposed that transcription of the upstream lncRNA interferes with expression
of the downstream mRNA genes by displacing the activating transcription factor Pho7 from its
binding site(s) in the mRNA promoters. The key discoveries underlying the present proposal are
our findings that: (i) 3’-processing and transcription termination is a control point in the lncRNA-
mediated repression of 3’-flanking gene expression, and (ii) Pho1 expression from the prt–pho1
locus is a sensitive read-out of cellular influences on termination. Based on these findings, we
hypothesize that IPP dynamics affect 3’-processing/transcription termination and influence
poly(A) site usage. Specific aims are to: (1) use genetic array analyses and reveal the extent to
which the functions of 3’ processing/transcription termination factors, the RNA Pol II CTD, and
factors involved in sculpting the CTD phosphorylation array depend on IPP levels; (2) assess –
at the genome-wide level – the impact of IPP dynamics on gene expression and 3’-end formation,
by analyzing mRNA and nascent RNA profiles and mapping poly(A) sites in wild-type cells and in
cells with altered IPP levels; and (3) explore mechanisms by which IPPs influence Pol2
transcription termination. Using in vitro synthesized IPPs, we will test whether components of the
3’-processing/transcription termination machinery are targets for pyrophosphorylation and
whether IPPs affect the activities of CTD kinases. We expect to gain new and general insights
into the role of these important signaling molecules in gene expression, and to illuminate the
signal transduction pathway involved in fission yeast phosphate homeostasis.

## Key facts

- **NIH application ID:** 10136034
- **Project number:** 5R01GM134021-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** BEATE SCHWER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $339,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136034

## Citation

> US National Institutes of Health, RePORTER application 10136034, Inositol pyrophosphate dynamics affect RNA 3'-processing/transcription termination (5R01GM134021-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10136034. Licensed CC0.

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