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

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $364,425

## Abstract

ABSTRACT
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. A role for IPPs in phosphate sensing and phosphate homeostasis is documented in fungi, plants, and
humans. Cells respond to phosphate limitation by inducing the transcription of phosphate acquisition genes, yet
the mechanisms by which this is achieved differ in each taxon. The phosphate (PHO) 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 RNA polymerase II (Pol2)
transcription in cis of a long noncoding (lnc) RNA from the respective 5' flanking genes prt, prt2, and nc-tgp1.
lncRNA transcription across the PHO mRNA promoter displaces the activating transcription factor Pho7 and
thereby interferes with PHO mRNA expression. The system of lncRNA-mediated transcriptional interference is
sensitive to genetic manipulations that influence 3’-processing/termination. Mutations that elicit “precocious”
lncRNA 3'-processing/termination in response to poly(A) signals upstream of the mRNA promoters lead to de-
repression of pho1, whereas genetic changes that diminish lncRNA termination hyper-repress pho1 expression.
We have exploited this system to discover novel influences on 3’-processing and Pol2 termination. We showed
that: (i) lncRNA transcription is subject to metabolite control by inositol pyrophosphate 1,5-IP8, which acts as an
agonist of precocious 3'-processing/termination; (ii) Spx1, which is composed of an SPX domain and a RING E3
ligase domain, is a likely mediator of IP8 signaling to the 3'-processing/termination machinery; (iii) the 14-3-3
protein Rad24 antagonizes precocious 3’-processing/termination in a manner that depends on its phosphate
binding site; and (iv) Pol2 termination can be enhanced via a gain-of-function mutation in the essential
termination factor Seb1. Specific aims are: (1) to identify targets of the Spx1 E3 ubiquitin ligase (via TULIP2
tagging and mass spectrometry); and to test whether pyrophosphorylation of (or IP8 binding to) components of
the Pol2 machinery contributes to the effects of IP8 on 3’-processing/termination; (2) to leverage new analytical
methods to assess IPP abundance and isoform distribution in fission yeast strains where genetics predicts
changes in IPP content, and to investigate whether and how phosphate starvation impacts cellular IPP content;
(3) To probe the mechanism by whi...

## Key facts

- **NIH application ID:** 10823283
- **Project number:** 5R01GM134021-06
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** BEATE SCHWER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $364,425
- **Award type:** 5
- **Project period:** 2019-08-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823283

## Citation

> US National Institutes of Health, RePORTER application 10823283, Inositol pyrophosphate dynamics affect RNA 3'-processing/transcription termination (5R01GM134021-06). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10823283. Licensed CC0.

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