# Regulation Of Metabolism And Gene Expression By Iron-Sulfur Clusters - Supplement

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $68,795

## Abstract

Project Abstract from Original Award (bold text added for emphasis related to the equipment request)
Iron-sulfur clusters (ISCs) are essential protein cofactors whose dysregulation is linked to a wide range of
debilitating diseases including Friedreich’s ataxia. This pathology is due in part to the use of ISCs in iron-
responsive proteins (IRPs), which control the translation of mRNAs in the iron-starvation response. We recently
found that by suppressing ISC biosynthesis we can robustly activate this IRP-mediated iron-starvation response,
sensitizing cancer cells to cell death by ferroptosis. Our preliminary data, which form the premise of our
application, point to an unexpected mode of IRP2 regulation by ISCs and demonstrate that the mechanism by
which ISCs modulate the iron-starvation response, and therefore impact human disease, remains unclear. Our
long-term goal is to dissect the mechanisms by which ISCs regulates cellular responses to changing
iron and oxygen availability and how this response is mediated by IRPs. We anticipate that these discoveries
will lead to the identification of pathologies for diseases where prior ISC involvement was unclear, to new
treatments for diseases of ISC dysregulation, and will facilitate novel methods to sensitize cancer cells to
ferroptosis. The objective of this grant is to dissect how ISCs control IRP2 activation and to comprehensively
define the targets of IRP1 and IRP2 and the conditions under which they are activated. Our overarching
hypothesis is that ISCs integrate iron and oxygen level inputs to effect specific translational responses
via differential regulation of IRPs. Our rationale is that identification of the specific mechanisms by which IRPs
are activated and the targets that they activate will enable the discovery of novel strategies to treat cancer and
disorders of ISC metabolism. Our specific aims will test the following hypotheses: (Aim 1) ISCs can activate the
iron-starvation response through an IRP2-mediated mechanism; (Aim 2) IRPs exhibit differential IRE binding
in response to iron and oxygen level modulation. Upon completion of these aims we will (1) gain an
understanding of how cells sense iron and oxygen levels and integrate these inputs using ISC sensors
and (2) identify IRP regulated target genes and the conditions in which they are regulated. This contribution is
significant because dysregulation of IRPs occurs frequently in human pathologies, and inducing activation of the
iron starvation response sensitizes cancer cells to ferroptotic cell death. This research is innovative because we
challenge paradigms in cellular iron-sensing to arrive at a comprehensive mechanism by which cells respond to
changes in the level of this important nutrient, and because we utilize heretofore unique approaches to identify
RNAs regulated by the iron starvation response and define their activation by upstream stimuli. The outcomes
of this study promise disrupt our understanding of iron sensing and...

## Key facts

- **NIH application ID:** 10669888
- **Project number:** 3R01GM132491-03S2
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Richard Lewis Possemato
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $68,795
- **Award type:** 3
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10669888

## Citation

> US National Institutes of Health, RePORTER application 10669888, Regulation Of Metabolism And Gene Expression By Iron-Sulfur Clusters - Supplement (3R01GM132491-03S2). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10669888. Licensed CC0.

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