# DMA-Tudor interaction modules: a novel approach to Survival Motor Neuron protein (SMN) and Cajal body function

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $444,314

## Abstract

Survival Motor Neuron protein (SMN) deficiencies cause Spinal Muscular Atrophy (SMA), the most common
genetic cause of infant and toddler mortality. Although SMN has been implicated in transcription, RNA
processing and translation, the molecular basis of motoneuron loss is still unknown. We recently discovered a
novel activity of SMN: biomolecular condensation caused by SMN’s globular tudor domain (SMNTud), which
binds ligands modified by dimethylarginine (DMA). Although there are hundreds of DMA-modified proteins
in cells, the correspondence between tudor domains and their DMA ligands remains unknown. This
understudied post-translational modification is potentially dynamic and has emerging roles in multiple
neurological diseases through the altered functions of cellular compartments known as biomolecular
condensates (BMCs). Our central hypothesis is SMNTud binding to DMA ligands plays critical roles in cellular
organization, which are especially vulnerable in the neuromuscular system.
Our findings highlight a critical need to comprehensively determine the DMA ligands of SMNTud and the activities
of the interaction modules they form. SMN is diffusely cytoplasmic and present in nuclear BMCs called Cajal
bodies, which are essential for embryonic development. Cajal bodies are scaffolded by a known SMNTud ligand
and altered in SMA. During stress, SMN forms BMCs in the cytoplasm. Our preliminary results directly
implicate DMA binding and biomolecular condensation in SMA, because SMNTud activity was blocked by a
single amino acid mutation, E134K, that blocks binding to DMA ligands and causes SMA. Chemical inhibitors
of DMA drastically altered the composition and substructure of Cajal bodies, which we determined for the first
time with our collaborator and co-I, Dr Joerg Bewersdorf. The identities of the full complement of DMA ligands
that bind SMNTud and those that affect Cajal bodies have been unknown until now. Our preliminary data reveal
~70 novel and specific SMNTud ligands, indicating that new insights relevant to SMA are within our grasp.
The overall objectives of this new application are to (i) identify the DMA ligands of SMNTud that mediate
biomolecular condensation, (ii) understand the dynamicity of asymmetric (aDMA) and symmetric (sDMA)
installed by arginine methyltransferases and removed by demethylases with respect to the structure and
function of BMCs, and (iii) reveal novel SMN functions by leveraging DMA-SMNTud interaction modules. Our
rationale is that objectives concerning DMA-SMNTud interaction modules will be most accessible to rigorous
analysis through a combination of biochemistry and state-of-the-art imaging, using mouse and zebrafish cells
and tissues, including motoneurons, with which we have expertise. If achieved, our aims will discover novel
SMN binding partners and functions of SMNTud in biomolecular condensation. The regulatory potential and
dynamicity of the DMA modification, a source of tissue specificity and disease etio...

## Key facts

- **NIH application ID:** 10662555
- **Project number:** 5R01NS128358-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Karla M Neugebauer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $444,314
- **Award type:** 5
- **Project period:** 2022-07-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10662555

## Citation

> US National Institutes of Health, RePORTER application 10662555, DMA-Tudor interaction modules: a novel approach to Survival Motor Neuron protein (SMN) and Cajal body function (5R01NS128358-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10662555. Licensed CC0.

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