# Defining Activities of KDMS Essential to Development and Viability

> **NIH NIH F31** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $48,974

## Abstract

ABSTRACT
The Lysine demethylase 5 (KDM5) family of transcriptional regulators are important for normal development,
and their dysregulation is a key driver of intellectual disability and several forms of cancer. Most work to-date
has focused on the histone demethylase activity of KDM5 proteins, which targets the active chromatin mark
H3K4me3. However, KDM5 proteins can also regulate transcription through non-enzymatic mechanisms. While
KDM5 is essential for development, its demethylase activity is not required, as is demonstrated by the viability
of demethylase-dead adult flies. In this work, we will examine essential functions of KDM5 via a novel truncation
allele, kdm5Q19, which does not alter demethylase activity. kdm5Q19 inserts a stop codon in a previously
unrecognized, evolutionarily conserved, motif within an intrinsically disordered region of KDM5 at the C-terminus.
kdm5Q19 animals do not survive to adulthood, which is distinct from null, demethylase dead, and other mutants
generated in our lab, suggesting that the motif disrupted by the truncation has an essential as-yet-unknown role
in normal KDM5 function. To further dissect the molecular activities of this region of KDM5, we generate
additional alleles of kdm5 to refine the critical region(s) of the protein and assess viability and changes to
transcription.
In this work, we will (1) define essential regions within KDM5 required for viability, and to characterize their roles
in development (2) define the essential molecular functions imparted by the C-terminus of KDM5. Together,
these studies will refine the critical region(s) of the C-terminus of KDM5, and define the normal role of these
regions in regulating transcription.

## Key facts

- **NIH application ID:** 10831837
- **Project number:** 5F31GM150194-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Melissa Castiglione
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-03-30 → 2025-03-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831837

## Citation

> US National Institutes of Health, RePORTER application 10831837, Defining Activities of KDMS Essential to Development and Viability (5F31GM150194-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10831837. Licensed CC0.

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