# Interdomain crosstalk in MORC3

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $318,777

## Abstract

Project Summary
 Microrchidia 3 (MORC3) has been linked to cancer-associated inflammations. Recent
studies from our group demonstrate that MORC3 is deregulated in patients with Down
syndrome (DS), however the precise role of MORC3 in disease or in normal cellular processes
remains poorly understood. Our preliminary data show that MORC3 has an intrinsic ATPase
activity and that the catalytic ATPase domain binds to DNA, whereas the adjacent CW domain
recognizes histone H3 and mediates the ATPase activity of MORC3. The molecular
mechanisms underlying these novel functions of MORC3 are unclear and will be elucidated in
the proposed studies. We hypothesize that the DNA-stimulated ATPase activity of MORC3 is
mediated through histone-binding activity of the CW domain, which in the MORC3 inactive
state, binds to and autoinhibits the ATPase domain; and that PTMs of histone H3 alter binding
of CW and fine-tune the ATPase activity of MORC3. We aim to define the molecular basis and
functional significance of the multivalent engagement of MORC3 with chromatin and to
understand the mechanism of its autoregulation. By establishing the biological role and
obtaining the mechanistic details, we will learn how this fundamental chromatin remodeling
component can be controlled.
 In this research we will employ a powerful combination of in vitro and in vivo approaches
to examine a newly identified epigenetic regulatory mechanism. We integrate X-ray
crystallographic, advanced Förster Resonance Energy Transfer, NMR spectroscopic and high-
throughput technological experiments with molecular and cell biology tools to gain insight into
the role of the ATPase and CW domains in biological activities of MORC3.
 In-depth structural, biochemical and functional characterization of MORC3 will have
significant impact on chromatin biology and basic molecular biology of chromatin-remodeling
enzymes. It will also aid to our understanding of the epigenetic-driven signaling events that are
deregulated in DS and other human diseases.

## Key facts

- **NIH application ID:** 9989134
- **Project number:** 5R01GM125195-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** TATIANA G KUTATELADZE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $318,777
- **Award type:** 5
- **Project period:** 2017-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989134

## Citation

> US National Institutes of Health, RePORTER application 9989134, Interdomain crosstalk in MORC3 (5R01GM125195-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9989134. Licensed CC0.

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